In addition to the many scientific publications listed here, the BCERP has also developed many outreach and educational materials.
A progress report summarizing the first phase of the program was developed in 2009. View the progress report (PDF format).
||To access a document using its Digital Object Identifier (DOI), go to http://dx.doi.org/ and type in the DOI name.
||You can use the PMID # to find the article
on at www.pubmed.com.
Aupperlee MD, Zhao Y, Tan YS, Leipprandt JR, Bennett J, Haslam SZ, Schwartz RC. (2014) Epidermal growth factor receptor (EGRF)-signaling is a key mediator of hormone-induced leukocyte infiltration in the pubertal female mammary gland. Endocrinology published online ahead of print April 2, 2014 doi: dx.doi.org/10.1210/en.2013-1933 (article summary)
Vangeepuram N, McGovern KJ, Teitelbaum S, Glavez MP, Pinney SM, Biro FM, Kushi LH, Wolff MS (2014) Asthma and physical activity in multiracial girls from three US sites. Journal of Asthma 51(2):193-9. doi: 10.3109/02770903.2013.853081. Epub 2013 Nov 15.
Allicock M, Graves N, Gray K, Troester MA. African American Women's Perspectives on Breast Cancer: Implications for Communicating Risk of Basal-like Breast Cancer. Journal of Health Care for the Poor and Underserved 24.2 (2013): 753-767 (article summary)
Aupperlee MD, Leipprandt JR, Bennett JM, Schwartz RC, Haslam SZ.(2013) Amphiregulin mediates progesterone-induced mammary ductal development during puberty. Breast Cancer Research 2013, 15:R44 doi:10.1186/bcr3431. PMID: 23705924 (article summary)
Biro FM, Greenspan LC, Galvez MP, Pinney SM, Teitelbaum S, Windham GC, Deardorff J, Herrick RL, Succop PA, Hiatt RA, Kushi LH, Wolff MS. Onset of breast development in a longitudinal cohort. Pediatrics. 2013; 1321019-27. doi: 10.1542/peds.2012-3773
Cheung, K.J., E. Gabrielson, Z. Werb & A. J. Ewald (2013). Collective invasion in breast cancer requires a conserved basal epithelial program. Cell. In press
Hillman JB, Huang B, Pinney SM, Biro FM (2013) Early Pubertal Development and Insulin Sensitivity among School-Aged Girls:
Mediation Via Adiposity. J Pediatr Adolesc Gynecol 26:47-50
Lemieux, G A, M. J. Keiser, M. F. Sassano, C. Laggner, F. Mayer, R. J. Bainton, Z. Werb, B. L. Roth, B. K. Shoichet & K. Ashrafi (2013). Human molecular pharmacology identifies feeding regulatory pathways in C. elegans. PLoS Biol. In press.
Mervish NA, Gardiner EW, Galvez MP, Kushi LH, Windham GC, Biro FM, Pinney SM, Rybak ME, Teitelbaum SL, Wolff MS. Dietary flavonol intake is associated with age of puberty in a longitudinal cohort of girls. Published online by Nutrition Research, May 31, 2013.
Pinney SM, Biro FM, Windham GC, Herrick RL, Yaghjyan L, Calafat AM, Succop P, Sucharew H, Ball KM, Kato K, Kushi LH, Bornschein R. Serum biomarkers of polyfluoroalkyl compound exposure in young girls in Greater Cincinnati and the San Francisco Bay Area, USA, Environmental Pollution, Volume 184, January 2014, Pages 327-334, http://dx.doi.org/10.1016/j.envpol.2013.09.008. Published online 10/03/13. (article summary)
Plaks V, Koopman CD, Werb Z (2013). Circulating Tumor Cells, Science, 341, 1186. doi: 10.1126/science.1235226
Smits BMG, Haag JD, Rissman AI, Sharma D, Tran A, et al. (2013) The Gene Desert Mammary Carcinoma Susceptibility Locus Mcs1a Regulates Nr2f1Modifying Mammary Epithelial Cell Differentiation and Proliferation. PLoS Genet 9(6): e1003549. doi:10.1371/journal.pgen.1003549.
Sundaram S, Freemerman AJ, Johnson AR, Milner JJ, McNaughton KK, Galanko JA, Bendt KM, Darr DB, Perou CM, Troester MA, Makowski L (2013) Role of HGF in obesity-associated tumorigenesis: C3(1)-TAg mice as a model for human basal-like breast cancer. Breast Cancer Research and Treatment vol 142 3:489-503. doi: 10.1007/s10549-013-2741-5 (article summary)
Zhao Y, Tan YS, Aupperlee MD, Langohr IM, Kirk EL, Troester MA, Schwartz RC, Haslam SZ. (2013) Pubertal high fat diet: effects on mammary cancer development. Breast Cancer Research. 15(5):R100 (article summary) (press release)
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Betancourt AM, Wang J, Jenkins S, Mobley J, Russo J, Lamartiniere CA. Altered carcinogenesis and proteome in mammary glands of rats after prepubertal exposures to the hormonally active chemicals bisphenol a and genistein. J Nutr. 2012 Jul;142(7):1382S-8S. Epub 2012 May 30.
Biro FM, Greenspan LC, Galvez MP. Puberty in girls of the 21st century. J Pediatr Adolesc Gynecol. 2012 Oct;25(5):289-94. doi: 10.1016/j.jpag.2012.05.009. Epub 2012 Jul 27. PMID:22841372
Brauer Ha, Makowski L, Hoadley KA, et al.Impact of Tumor Microenvironment and Epithelial Phenotypes on Metabolism in Breast Cancer. Clin Cancer Res Published OnlineFrist Decembbre 12, 2012. doi:10.1158/1078-0432.CCR-12-2123
Cohn BA, Terry MB, Plumb M, Cirillo PM. Exposure to polychlorinated biphenyl (PCB) congeners measured shortly after giving birth and subsequent risk of maternal breast cancer before age 50.
Breast Cancer Res Treat. 2012 Sep 28. [Epub ahead of print] PMID:23053646
Deardorff J, Fyfe M, Ekwaru JP, Kushi LH, Greenspan LC, Yen IH. Does Neighborhood Environment Influence Girls' Pubertal Onset? Findings from a Cohort Study. BMC Pediatrics 2012, 12:27
Ewald AJ, Huebner RJ, Palsdottir H, Lee JK, Perez MJ, Jorgens DM, Tauscher AN, Cheung KJ, Werb Z, Auer M. Mammary collective cell migration involves transient loss of epithelial features and individual cell migration within the epithelium. J Cell Sci. Advance Online Publication February 17, 2012. doi: 10.1242/jcs.096875
Jenkins S, Betancourt AM, Wang J, Lamartiniere CA.
Endocrine-active chemicals in mammary cancer causation and prevention.
J Steroid Biochem Mol Biol. 2012 Apr;129(3-5):191-200. Epub 2011 Jun 23. Review. PMID:21729753
Justice M, Greenburg G, Hernick AD, Monroe P. Disseminating Research Findings to the Community: Breast Cancer Advocates Conduct Education Forums. Environmental Justice 2012, 5(3):128-132. doi:10.1089/env.2011.0008
LaPlante C, Smith SW, Kotowski M, Nazione S, Stohl C, Prestin A, So J, Nabi R. An Initial Investigation into Naturally Occurring Loss- and Gain-Framed Memorable Breast Cancer Messages. Communication Quarterly, 60, 1-16. PMC3332232
Littlepage LE, Adler AS, Kouros-Mehr H, Huang G, Chou J, Krig SR, Griffith OL, Korkola JE, Qu K, Lawson DA, Xue Q, Sternlicht MD, Dijkgraaf GJP, Yaswen P, Rugo HS, Sweeney CA, Collins CC, Gray JW, Chang HY, Werb Z.. The Transcription Factor ZNF217 Is a Prognostic
Biomarker and Therapeutic Target during Breast Cancer Progression. Cancer Discovery 2012;2:638-651. Published Online First May 10, 2012, doi: 10.1158/2159-8290.CD-12-0093
Lu P, Weaver VM, Werb Z. The extracellular matrix: A dynamic niche in cancer progression. J Cell Biol. 196(4):395-406
Mervish N, Blount B, Valentin-Blasini L, Brenner B, Galvez MP, Wolff MS, Teitelbaum SL. Temporal variability in urinary concentrations of perchlorate, nitrate, thiocyanate and iodide among children. J Expo Sci Environ Epidemiol. 2012 22(2):212-8. DOI: 10.1038/jes.2011.44 [Epub ahead of print] PMID: 22166811, PMCID: PMC3288286
Nguyen-Ngoc KV, Cheung KJ, Brenot A, Shamir ER, Gray RS, Hines WC, Yaswen P, Werb Z, Ewald AJ. ECM microenvironment regulates collective migration and local dissemination in normal and malignant mammary epithelium. PNAS, 2012 109 (39) E2595–E2604. published online August 23, 2012, doi:10.1073/pnas.1212834109
Osuch J, Silk K, Price C, Barlow J, Miller K, Hernick A, Fonfa A. A Historical Perspective on Breast Cancer Activism in the United States: From Education and Support
to Partnership in Scientific Research. Journal of Women's Health 2012 21(3):355-62. DOI: 10.1089/jwh.2011.2862
Partane, JI, Tervonen T, Myllynen M, Lind E, Imai M, Katajisto P, Dijkgraaf GJP, Kovanen P, Mäkelä T, Werb Z & Klefstrom J. Tumor suppressor function of Liver Kinase B1 (Lkb1) is linked to regulation of epithelial integrity. PNAS 2012 109 (7) E388–E397; published ahead of print January 20, 2012, doi:10.1073/pnas.1120421109
Pirone JR, D'Arcy M, Stewart DA, Hines WC, Johnson M, Gould MN, Yaswen P, Jerry DJ, Schneider SS, Troester MA. Age-Associated Gene Expression in Normal Breast Tissue Mirrors Qualitative Age-at-Incidence Patterns for Breast Cancer. Cancer Epidemiol Biomarkers Prev. 2012 Oct;21(10):1735-44. doi: 10.1158/1055-9965.EPI-12-0451. Epub 2012 Aug 2. PMID:22859400
Román-Pérez E, Casbas-Hernández P, Pirone JR, Rein J, Carey LA, Lubet RA, Mani SA, Amos KD,Troester MA. Gene expression in extratumoral microenvironment predicts clinical outcome in breast cancer patients. Breast Cancer Res. 2012 Mar 19;14(2):R51. PMID:22429463
Sampey BP, Freemerman AJ, Zhang J, Kuan P-F, Galanko JA, O'Connell TM, Ilkayeva OR, Muehlbauer MJ, Stevens RD, Newgard CB, Brauer HA, Troester MA, Makowski L. Metabolomic Profiling Reveals Mitochondrial-Derived Lipid Biomarkers That Drive Obesity-Associated Inflammation. PLoS ONE 7(6): e38812. DOIi:10.1371/journal.pone.0038812
Stewart DA, Yang Y, Makowski L, Troester MA.Basal-like breast cancer cells induce phenotypic and genomic changes in macrophages. Mol Cancer Res. 2012 Jun;10(6):727-38. Epub 2012 Apr 24.PMID:22532586
Teitelbaum SL, Mervish N, L Moshier E, Vangeepuram N, Galvez MP, Calafat AM, Silva MJ, L Brenner B, Wolff MS. Associations between phthalate metabolite urinary concentrations and body size measures in New York City children. Environ Res. 2012 Jan 3. [Epub ahead of print] PMID: 22222007
Vangeepuram N, Galvez MP, Teitelbaum SL, Brenner B, Wolff MS. The Association between Parental Perception of Neighborhood Safety and Asthma Diagnosis in Ethnic Minority Urban Children. J Urban Health. 2012 Oct;89(5):758-68. doi: 10.1007/s11524-012-9679-5
Vangeepuram N, Mervish N, Galvez MP, Brenner B, Wolff MS. Dietary and Physical Activity Behaviors of New York City Children From Different Ethnic Minority Subgroups. Acad Pediatr. 2012 Sep 15. pii: S1876-2859(12)00190-8. doi: 10.1016/j.acap.2012.06.014. [Epub ahead of print]
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Sarah Jenkins, Wang J, Eltoum I, Desmond R, Lamartiniere CA. (2011) Chronic Oral Exposure to Bisphenol A Results in a Nonmonotonic Dose Response in Mammary Carcinogenesis and Metastasis in MMTV-erbB2 Mice. Environ Health Perspect 119(11): doi:10.1289/ehp.1103850
Khokha, R., & Z. Werb (2011). Mammary gland reprogramming: metalloproteinases couple form with function. Cold Spring Harb. Perspect. Biol. 3:a004333. doi: 10.1101/cshperspect.a004333 [2010 Nov 24. Epub ahead of print]. PMID:21106646
Lemieux, G. A., J. Liu, N. Mayer, R. J. Bainton, K. Ashrafi & Z. Werb (2011). A whole organism screen identifies novel regulators of fat storage. Nature Chem. Biol. 7: 206-213. [Mar 13. Epub ahead of print]. PMID: 21390037
Jose I. Lopez, Inkyung Kang, Weon-Kyoo You, Donald M. McDonald and Valerie M. Weaver. In situ force mapping of mammary gland transformation Integr. Biol., 2011, 3, 910-921. PMID: 21842067
Lu, P., K. Takai, V. M. Weaver & Z. Werb (2011). Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb. Perspect. Biol. doi: 10.1101/cshperspect.a005058. [Epub ahead of print]. PMID: 21917992
Nguyen DH, Oketch-Rabah HA, Illa-Bochaca I, Geyer FC, Reis-Filho JS, Mao J-H, Ravani A, Zavadil J, borowsky AD, Jerry DJ, Dunphy KA, Seo JH, Haslam S, Medina D, Barcellos-Hoff MH. (2011) Radiation acts on the microenvironment to affect
breast carcinogenesis by distinct mechanisms
that decrease cancer latency and affect tumor type. Cancer Cell 19:640-651. DOI 10.1016/j.ccr.2011.03.011 (article summary)
Janet R Osuch, Silk K, Price C, Barlow J, Miller K, Hernick A, Fonfa A. (2011) A Historical Perspective on Breast Cancer Activism in the United States: From Education and Support to Partnership in Scientific Research. J Womens Health (Larchmt) Dec 1 [epub ahead of print]
Moral R, Santucci-Pereira J, Wang R, Russo IH, Lamartiniere CA, Russo J (2011) In utero exposure to butyl benzyl phthalate induces modifications in the morphology and the gene expression profile of the mammary gland an experimental study in rats. Environmental Health 2011, 10:5
Vangeepuram N, Teitelbaum S, Galvez M, Brenner B, Doucette J, Wolff MS. (2011) Measures of Obesity Associated with Asthma Diagnosis in Ethnic Minority Children. J Obesity, 2011: 517417, doi:10.1155/2011/517417, PMCID: PMC3136214
Wang J, Betancourt AM, Mobley JA, Lamartiniere CA. Proteomic discovery of genistein action in the rat mammary gland J Proteome Res. 2011 Apr 1;10(4):1621-31. Epub 2011 Feb 22. PMID:21254785
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Atkin CK & Smith SW. (2010) Improving Communication Practices to Reduce Breast Cancer Environmental Risks, Health Communication, 25:587-588. doi:10.1080/10410236.2010.496836
Barcellos-Hoff MH. (2010) Stromal Mediation of Radation Carcinogen. J Mammary Gland Biol Neoplasia 15:381-387. DOI 10.1007/s10911-010-9197-6
Betancourt AM, Eltoum IA, Desmond RA, Russo J, Lamartiniere CA. In utero exposure to bisphenol A shifts the window of susceptibility for mammary carcinogenesis in the rat. Environ Health Perspect. 2010 Nov;118(11):1614-9. PMID:20675265
Betancourt AM, Mobley JA, Russo J, Lamartiniere CA.Proteomic analysis in mammary glands of rat offspring exposed in utero to bisphenol A. J Proteomics. 2010 Apr 18;73(6):1241-53. Epub 2010 Feb 26. PMID:20219716
Biro FM, Galvez M, Greenspan LC, Succop P, Vangeepuram N, Pinney S, Teitelbaum S, Windham G, Kushi L, Wolff MS. (2010) Pubertal assessment methodology and baseline characteristics in a mixed longitudinal study of girls. Pediatrics 126, Sept 2010. (show more/hide)
The purpose of this study was to describe the assessment methods and maturation status of the girls in the Breast Cancer and the Environment Research Centers, at baseline recruitment, and at ages 7 and 8 years. The proportion of girls who had attained breast stage 2 varied by age, race/ethnicity, BMI percentile, and site. At age 7 years, 10.4% of white, 23.4% of black, non-Hispanic, and 14.9% of Hispanic girls attained breast stage 2 or greater; and at age 8 years, 18.3%, 42.9%, and 30.9%, respectively, attained breast stage 2 or greater. The proportion of white participants who had breast development during ages 7 and 8 years is greater than that reported from that reported in the Pediatric Research in the Office Settings (PROS), published by Herman-Giddens in 1997. This study suggests that white girls enter at younger ages than previously published. Future studies will report on those factors which lead to earlier maturation.
Clark-Hitt R, Dean M, Smith SW, Nazione S, Atkin CK & Whitten P. (2010) Relative Frequency of Breast Cancer Website Information Topics: Environmental Risk, Prevention, Detection, Treatment, Awareness, Social Support, and Survivorship, Journal of Health and Mass Communication, 2:36-55.
Chou J, Provot S, and Werb Z. (2010) GATA3 in Development and Cancer Differentiation: Cells GATA Have It! J. Cell. Physiol. 222:42-49. PMID: 19798694
Deardorff J, Ekwaru JP, Kushi LH, Ellis BJ, Greenspan LC, Mirabedi A, Landaverde EG, Hiatt RA. (2010) Father Absence, Body Mass Index, and Pubertal Timing in Girls: Differential Effects by Family Income and Ethnicity. J Adol Health.
2011 48,5:441-447. Published online Sept 20, 2010. (show more/hide
) (article summary
) DOI: 10.1016/j.jadohealth.2010.07.032
Background: Many studies show links between father absence in the family and girls’ starting puberty at an early age. However, most research has focused on events that took place in the past, the age of first menstruation, and did not account for Body Mass Index (body weight and height), ethnicity and income. This study resolves these scientific gaps.
Study Design: This was a study of 444 6-8-year-old girls and their caregivers (96% of the caregivers were mothers) following the girls as they grow up and experience puberty. Data were collected every year in clinic, including weight, height and Tanner stage for breast and pubic hair. Caregivers reported on whether the girl’s biological father was living in the home and demographic information such as the girl’s age, race, ethnicity, household income, etc. This report focuses on the assessment of father absence at the first clinic appointment and two years of follow-up appointments for markers indicating the start of puberty. Cox proportional hazards regression models were used to test whether father absence at the first clinic appointment predicted the start of puberty by the second clinic appointment. Body Mass Index (body weight and height) was assumed to affect when girls started puberty. Differences by ethnicity and income were examined. Ethnicities included non-Hispanic white, African-American or black, Hispanic or Latino, Asian-American or other. Higher income families were defined as households with an annual income of $50,000 or more and lower income families were defined as households with an annual income of less than $50,000.
Results: Father absence was highest among African Americans and lowest among non-Hispanic Whites. Mother’s age of first menstruation was not related to the age her daughter started puberty. The rate of developing pubic hair was much higher in African American girls compared to non-African Americans. Body Mass Index (body height and weight) was not related to father absence. Father absence was linked to an earlier age of developing breasts only in higher-income families but not in lower-income families. African American girls in higher income families developed pubic hair at earlier ages if there was no father present in the home.
Conclusions: Among girls from higher-income but not lower-income families, father absence is linked to an earlier age that girls start puberty. This was particularly true for African Americans in terms of pubic hair development. These effects are not explained by body weight. Future research is needed to identify other ways that father absence, ethnicity and income impact the start of puberty in girls.
Egeblad M, Nakasone ES, and Werb Z. (2010) Tumors as Organs: Complex Tissues that Interface with the Entire Organism. Developmental Cell 18:884-901
Galvez MP, Pearl M, Yen I. Childhood Obesity and the Built Environment: A Review of the Literature from 2008-2009. Curr Opin Pediatr; 22(2):202-7. 2010 PMC2896907
Hernick AD, Brown MK, Pinney SM, Biro FM, Ball KM, Bornschein RL (2010). Sharing Unexpected Biomarker Results with Study Participants (commentary). Environ Health Perspect 119(1): doi:10.1289/ehp.1001988 (article summary)
Kariagina A, Xie J, Leipprandt JR, Haslam SZ. (2010) Amphiregulin mediates estrogen, progesterone,
and EGFR signaling in the normal rat mammary gland
and in hormone-dependent rat mammary cancers. Horm Canc (2010) 1:229–244,
Leung C, Gregorich SE, Laraia BA, Kushi LH, Yen IH. (2010) Measuring the Neighborhood Environment: Associations with Young Girls' Energy Intake and Expenditure in a Cross-Sectional Study. Int J of Behavioral Nutrition and Phys Activity 7:52, doi:10.1186/1479-5868-7-52 (article summary)
Mukhopadhyay R, Costes SV, Bazarov AV, Hines WC, Barcellos-Hoff MH, and Yaswen P. (2010) Promotion of variant human mammary epithelial cell outgrowth by ionizing radiation: an agent-based model supported by in vitro studies. Breast Cancer Res. 2010 Feb 10;12(1):R11. doi:10.1186/bcr2477, PMID: 20146798 (article summary)
L. Karl Olson, Ying Tan, Yong Zhao, Mark D. Aupperlee, Sandra Z. Haslam. (2010) Pubertal Exposure to High Fat Diet Causes Mouse Strain-dependent Alterations in Mammary Gland Development and Estrogen Responsiveness. International Journal of Obesity 34(9):1415-1426
Santos SJ, Haslam SZ, Conrad SE. Signal transducer and activator of transcription 5a mediates mammary ductal branching and proliferation in the nulliparous mouse. Endocrinology. 2010 Jun;151(6):2876-85. Epub 2010 Apr 14.PMID:20392833
Smith SW, Hame LM, Kotowski MR, Nazione S, LaPlante C, Atkin CK, Stohl C & Skubisz C. (2010) Action tendency emotions associated with memorable breast cancer messages. Health Communication, 25:737-746. doi:10.1080/10410236.2010.521916
Windham GC, Pinney SM, Sjodin A, Lum R, Jones RS, Needham LL, Biro FM, Hiatt RA and Kushi LH. (2010) Body burdens of brominated flame retardants and other persistent organo- halogenated compounds and their descriptors in US girls. Environ. Res.
) (article summary
What and Why:
- A new study1 by CDPH scientists and collaborators is being published today to report levels of persistent chemicals measured in girls 6-9 years old because data has not previously been available for this age group in the U.S.
- The chemicals measured were chosen because they may act like hormones, potentially affecting development, and they stay in the environment for years. These include fire retardants, like the previously banned PCBs, and the newer PBDEs, as well as pesticides like DDT and its metabolite, DDE.
- Several types of chemicals in each of these groups were found in nearly all the girls.
- PBDE levels were generally higher in girls in California than Ohio [which supports a prior study showing higher PBDE levels in house dust in California and may indicate how the children are exposed]. California has stricter flammability standards than other states, requiring the addition of flame retardants to upholstered furniture to meet them.
- PBDE levels were higher on average than in a national sample of older children, 12-19 years, who were studied a few years earlier.
- PCBs and DDE tended to be higher in California than Ohio, but overall similar to the national sample of 12-19 year olds. This may reflect a greater proportion of immigrants in California from countries that still use these chemicals.
- Levels differed by race/ethnic group, such that Blacks had higher levels of PBDEs, but lower levels of PCBs and DDE, than Whites.
- As was already known from other studies, PCB and DDE levels were higher in girls that were breast-fed (because they concentrate in fat). PBDE levels did not vary much by breast-feeding, so levels most likely reflect more recent exposures in the diet or from dust. Breast-feeding is still recommended because of other benefits to children.
- This study did not look at health effects of these chemicals, but will examine reproductive development and growth as next steps.
- When the California Environmental Contaminant Biomonitoring Program, a multi-agency effort, is up and running, some of these same chemicals will be measured on a regular basis.
Wolff MS, Teitelbaum SL, Pinney SM, Windham G, Liao L, Biro F, Kushi LH, Erdmann C, Hiatt RA, Rybak ME, Calafat AM, BCERC. (2010) Investigation of Relationships between Urinary Biomarkers of Phytoestrogens, Phthalates, and Phenols and Pubertal Stages in Girls. Environ Health Perspect 118(7): 1039-1046, doi:10.1289/ehp.0901690
Zhao, Y, Tan YS, Haslam, SZ, Yang C (2010). Perfluorooactanoic acid effects on steroid hormne and growth factor levels mediate stimulation of peripubertal mammary gland development om C57 BL/6 mice. Toxicol Sci 115:214-224. [Epub ahead of print, Jan 29] DOI: 10.1093/toxsci/kfq030
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Aupperlee MD, Drolet A, Durairaj S, Wang W, Schwartz R, Haslam S. (2009) Strain-specific differences in the mechanisms of progesterone regulation of murine mammary gland development. Endocrinology 150:1485-1494
Barcellos-Hoff MH and Nguyen DH. (2009) Radiation Carcinogenesis in Context: How Do Irradiated Tissues Become Turmors? Health Physics 97:446-457
Biro FM, Wolff MS, Kushi L. (2009) Impact of Yesterday's Genes and Today's Diet and Chemicals on Tomorrow's Women. J of Ped and Adolescent Gynecology 22:3-6
Fernandez-Gonzalez R, Illa-Bochaca I, Welm B, Fleisch M, Werb Z, Ortiz de Solorzano C, Barcellos-Hoff M. (2009) Mapping mammary gland architecture using multi-scale in situ analysis. Integrative Biol 1:80-89 DOI:10.1039/b816933k
Fernandez-Gonzalez R, Illa-Bochaca I, Shelton D, Welm B, Ortiz de Solorzano C, Barcellos-Hoff M. (2009) In situ analysis of cell populations: long-term label-retaining cells. In Methods in Molecular Biology: Protocols for Adult Stem Cells, I Conboy, D Schaffer, MH Barcellos-Hoff, S Li, editors. Humana Press, Totowa, NJ
Fernandez-Gonzalez R, Illa-Bochaca I, Shelton D, Welm B, Ortiz de Solorzano C, Barcellos-Hoff M. (2009) Use of stem cell markers in dissociated mammary populations. In Methods in Molecular Biology: Protocols for Adult Stem Cells, I Conboy, D Schaffer, MH Barcellos-Hoff, S Li, editors. Humana Press, Totowa, NJ
Fernandez-Gonzalez R, Illa-Bochaca I, Shelton D, Welm B, Ortiz de Solorzano C, Barcellos-Hoff M. (2009) Limiting-dilution transplantation assays in mammary stem cell studies. In Methods in Molecular Biology: Protocols for Adult Stem Cells, I Conboy, D Schaffer, MH Barcellos-Hoff, S Li, editors. Humana Press, Totowa, NJ
Ford K, Khoury P, Biro F. (2009) Early Markers of Pubertal Onset: Height and Foot Size. Journal of Adolescent Health 44:500-501
Fournier MV, Fata J, Martin K, Yaswen P, Bissell M. (2009) Interaction of E-cadherin and PTEN regulates morphogenesis and growth arrest in human mammary epithelial cells. Cancer Res 69:4545-4552
Hiatt RA, Haslam SZ, Osuch J. (2009) The Breast Cancer and the Environment Research Centers: Transdisciplinary Research on the Role of the Environment in Breast Cancer Etiology. Envir Health Perspect 117:1814-1822. DOI:10.1289/ehp.0800120
Jenkins S, Raghuraman N, Eltoum I, Carpenter D, Russo J, Lamartiniere C. (2009) Oral exposure to bisphenol A increases dimethylbenzanthracene-induced mammary cancer in rats. Env Hlth Perspective 117:910-915 DOI:10.1289/ehp.11751
Medvedovic M, Gear R, Freudenberg J, Schneider J, Bornschein R, Yan M, Mistry M, , Hendrix H, Karyala S, Halbleib D, Heffelfinger S, Clegg D. (2009) Influence of fatty acid diets on gene expression in rat mammary epithelial cells. Physiol. Genomics 38:80-88 DOI:10.1152/physiolgenomics.00007.2009
Santos, S. J., M. D. Aupperlee, J. Xie, S. Durairaj, R. Miksicek, S. E. Conrad, J. R. Leipprandt, Y. S. Tan, R. C. Schwartz, and S. Z. Haslam. 2009. Progesterone receptor A-regulated gene expression in mammary organoid cultures. J. Steroid Biochem. and Molec. Biol. 5: 161-172.
Smith SW, Atkin C, Munday S, Skubisz C, Stohl C. (2009) The impact of personal and/or close relationship experience on memorable messages about breast cancer and the perceived speech acts of the sender. Journal of Cancer Education 24:129-134
Smith SW, Munday S, LaPlante C, Kotowski M, Atkin C, Skubisz C, Stohl C. (2009) Topics and sources of memorable breast cancer messages: their impact on prevention and detection behaviors. J of Health Communication 14:293-307
van Olphen J, Ottoson J, Green L, Barlow J, Koblick K, Hiatt R (2009). Evaluation of a Partnership Approach to Translating Research on Breast Cancer and the Environment. Progress in Community Health Partnerships: Research, Education, and Action 3:213-226
Yang CF, Tan Y, Harkema J, Haslam S. (2009) Differential effects of peripubertal exposure to perfluorooctanoic acid on mammary gland development in C57BL/6 and Balb/c mouse strains. Reproductive Toxicology 27:299-306 DOI:10.1016/j.reprotox.2008.110.003
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Atkin C, Smith S, Ferguson V, McFeters C (2008). A comprehensive analysis of breast cancer news coverage in leading media outlets. J of Health Communication 13:3-17. DOI: 10.1080/10810730701806912
Barcellos-Hoff MH. (2008) Cancer as an emergent phenomenon in radiation systems biology. Radiat Environ Biophys 47:33-38
Egeblad M, Ewald AJ, Askautrud HA, Truitt ML, Welm BE, Bainbridge E, Peeters G, Krummel MJ, Werb Z (2008). Visualizing Stromal Cell Dynamics in Different Tumor Microenvironments by Spinning Disk Confocal Microscopy. Disease Models & Mechanisms 1:155-167. doi:10.1242/dmm.000596
Ewald AJ, Brenot A, Duong M, Chan B, Werb Z (2008). Collective Epithelial Migration and Cell Rearrangements Drive Mammary Branching Morphogenesis. Developmental Cell 14:570-58. DOI:10.1016/j.devcel.2008.03.003 (show more/hide)
How the breast ducts, the branching tubes that will carry milk, grow during normal breast development during puberty is a major question being studied. To expand current knowledge of how mammary branching takes place in animals and humans, this research group took time-lapse movie images that monitored branching initiation, elongation, and splitting.
The investigators examined previously identified “crucial” proteins called growth factors and found that mammary ducts only branched when these proteins were close by. They also discovered that branching only takes place in special sites where there are multiple layers of tissue. Interestingly, similar multiple layers of cells are an early event in breast tumors formation. The new video methods developed for use in this study will be extremely useful in future studies that monitor cellular growth and proliferation and in understanding tumor progress.
Galvez MP, Morland K, Raines C, Kobil J, Siskind J, Godbold J, Brenner B. (2008) Race and Food Store Availability in an Inner City Neighborhood. Public Health Nutr 6:624-631
Kariagina A, Aupperlee M, Haslam S (2008). Progesterone receptor isoform functions in normal breast development and breast cancer. Crit Rev in Eucaryotic Gene Ex 18: 11-33. (show more/hide)
Progesterone acting through two isoforms of the progesterone receptor (PR), PRA and PRB, regulates proliferation and differentiation in the normal mammary gland in mouse, rat and human. Progesterone and PR have also been implicated in the etiology and pathogenesis of human breast cancer. The focus of this review is on recent advances in understanding the role of the PR isoform specific functions in the normal breast and in breast cancer. Also discussed is information obtained from rodent studies on the hormonal regulation of PR isoform expression in mammary gland, recent progress in unraveling the molecular mechanisms of P action via PR isoforms, comparison of human, mouse, and rat PR isoform expression, and possible relationship of PR isoform expression to normal mammary gland development in human, rat, and mouse. Studies of P action and PR isoform-specific functions in normal mammary gland and during tumor development in animal models can provide an important insight into breast cancer etiology. Most importantly, such studies may provide novel preventive, diagnostic, and therapeutic strategies to fight breast cancer.
Kouros-Mehr H, Bechis S, Slorach E, Littlepage L, Egeblad M, Ewald A, Pai S, Ho I, Werb Z (2008). GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model. Cancer Cell 13(2):141-152. DOI:10.1016/j.ccr.2008.01.011 PMID:18242514 (show more/hide)
Patients with metastatic breast cancer (cancer that spreads from the breast to other sites in the body), have an increased risk of mortality. Presently, estrogen-receptor status is the most common predictor of breast cancer survival. A tumor which responds to estrogen (estrogen-receptor positive) may be more easily treated with anti-estrogenic therapies, while a tumor which does not respond to estrogen (estrogen-receptor negative) may be more difficult to treat. New discoveries concerning a special protein called GATA-3 have provided clues about breast cancer prognosis and offer a possible explanation of carcinogenesis. GATA-3 levels in breast tissue are a more powerful predictor of breast cancer status than the current estrogen-receptor approach.
The research team studying the GATA factors found that low GATA-3 expression led to advanced cancers that are more prone to metastasis, while high GATA-3 expression was correlated with smaller tumor size that did not show metastatic capabilities. Replacing the GATA-3 in the low GATA-3 tumor stopped their metastasis. A better understanding of the GATA pathway offers hope in finally understanding the molecular mechanisms of breast cancer.
Kouros-Mehr H, Kim J, Bechis S, Werb Z (2008). GATA-3 and the regulation of the mammary luminal cell fate. Curr Opin Cell Biol 20(2):164-170. DOI:10.1016/j.ceb.2008.02.003 PMID:18358709
Lu P, Ewald AJ, Martin GR, Werb Z (2008). Genetic Mosaic Analysis Reveals FGF Receptor 2 Function in Terminal End Buds During Mammary Gland Branching Morphogenesis. Developmental Biology 321:77–87. doi:10.1016/j.ydbio.2008.06.005
Lu P and Werb Z. (2008) Patterning Mechanisms of Branched Organs. Science 322:1506-1509.
Moral R, Wang R, Russo I, Lamartiniere C, Pereira J, Russo J (2008). Effect of prenatal exposure to the endocrine disruptor bisphenol A on mammary gland morphology and gene exression signature. J of Endocrinology 196:101-112.
Santos SJ, Haslam S, Conrad S (2008). Estrogen and progesterone are critical regulators of Stat5a expression in the mouse mammary gland. Endocrinology 149:329-338. DOI:10.1210/en/2007-0594 (show more/hide)
Stat5a is a protein that is important for controlling growth and development of the mammary gland, and has also been implicated in breast cancer. Stat5a functions as a transcription factor that induces expression of genes, but in order to do so it must first be activated. In mammary cells, Stat5a is activated primarily via the hormone prolactin. Although the mechanisms that activate Stat5a are well understood, very little is known about those that regulate its expression in the mammary gland. In this report, sections of mouse mammary glands were stained for Stat5a protein in order to examine its levels throughout development. We found that it is not present before puberty, when estrogen (E) and progesterone (P) levels are low, but appears during puberty and is maintained in adult animals. When both E and P were eliminated from mice by removing the ovaries, Stat5a disappeared, and treatment with E+P was necessary to restore its expression to the level seen in intact, mature animals. Stat5a positive cells also contained receptors for both E and P, suggesting that its expression is directly regulated by these receptors in response to hormone treatment. Thus, these results identify a novel mechanism of in which E and P induce Stat5a expression, allowing for the protein to be subsequently activated by prolactin. The active protein is then able to regulate downstream genes in order to promote mammary gland development.
Sternlicht MD, Sunnarborg S. (2008) The ADAM17-amphiregulin-EGFR Axis in Mammary Development and Cancer. J Mamm. Gland Biol. Neoplasia 13:181-194 DOI:10.1007/s10911-008-9084-6 PMID:18470483
Teitelbaum SL, Britton J, Calafat A, Ye X, Silva M, Reidy J, Galvez M, Brenner B, Wolff M (2008). Temporal variability in urinary concentrations of phthalate metabolites, phytoestrogens and phenols among minority children in the United States. Environmental Research 106:257-269.
Volkman J, Silk K. (2008) Adolescent females and their mothers: Examining perceptions of the environment and breast cancer. Journal of Health Psychology 13:1180-1189
Welm BE, Dijkgraaf J, Bledau A, Welm A, Werb Z (2008). Lentiviral transduction of mammary stem cells for analysis of gene function during development and cancer. Cell Stem Cell 2:90-102. PMID:18371425 (show more/hide)
Transduction is the process of transferring genetic material from one organism to another with the help of a virus. This technique allows exclusive study of a single gene and enables researchers to determine its unique role. The mouse mammary gland is ideally suited for studying the function of individual genes, and a group of researchers have come up with a new way to study them.
The team infected the cell of breast ducts, called mammary epithelial cells, with a virus containing the individual gene of study. Their method turned out to be much more practical and effective than the existing approach, while also being more cost effective. Information gained from studies using this model supports the current theory that during formation of the extensively branched network of tubes during development of the breast, many mammary branches can arise from a single breast stem cell or several different stem cells can contribute to the formation of a single tube. This understanding will help us understand the origins of the breast tubes and how abnormal cells contribute to the pattern during the early stages of tumor formation.
Wetmur JG, Chen J (2008). An emulsion of PCR-based method for molecular haplotyping. In Environmental Genomics (Methods in Molecular Biology, vol 410) Martin, C., ed., Humana Press, Totowa, NJ.
Whitten P, Smith S, Munday S, LaPlante S (2008). Communication assessment of the most frequented breast cancer websites: Evaluation of design and theoretical criteria. Journal of Computer Mediated Communication, 13, 880-911. doi:10.1111/j.1083-6101.2008.00423.x
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In the normal mouse mammary gland progesterone (P) can cause cells to divide or change form through two progesterone receptor (PR) isoforms, PRA and PRB. PRA is the predominant isoform expressed in the adult virgin mouse, and PRB is predominantly expressed during pregnancy. In order to study the control of the PR isoforms by hormones and to examine the different functions of PRA and PRB, we removed the ovaries, which are the major source of hormone production, from adult mice and the mice were treated for 3, 5, or 10 days with estrogen (E), P, or estrogen + progesterone (E+P). We used a technique called immunohistochemistry to stain thin sections of mammary tissue with antibodies specific for PRA or PRB. This technique allowed us to investigate the regulation of PRA and PRB by hormones and to determine the role of PRA and PRB in cell turnover and overall changes in organization of the mammary gland. E treatment caused limited cell turnover that was only present after 5 days and was localized to the ends of ducts. P-induced cell turnover led to the formation of small buds, called sidebranches, off of the ducts and formation of grape-like clusters of cells called alveoli. However, the effect of E+P on sidebranching and formation of alveoli was greater. E increased PRA level, while P decreased PRA level. PRB expression was only detected following treatment with P or E+P. During sidebranching, PRA was the predominant PR isoform expressed. Cell turnover of both PRA expressing and PRA negative cells was responsible for P-induced sidebranching. In contrast, PRB was the predominant PR isoform expressed during formation of alveoli. Cell turnover of both PRB expressing and PRB negative cells was responsible for P-induced alveolar expansion. These results demonstrate that control of PRA and PRB levels by hormones in vivo occur differently and suggest that P induces cell turnover through PRA and PRB by direct and indirect mechanisms.
Brenner BL, Galvez M (2007). Community interventions to reduce exposure to chemicals with endocrine disrupting properties. In Endocrine-disrupting Chemicals: From Basic Research to Clinical Practice ed. Andrea C. Gore. Humana Press.
Claudio L (2007). Centered on breast cancer. Env Hlth Perspective 115(3):A132-133.
Fata JE, Mori H, Ewald A, Zhang H, Yao E, Werb Z, Bissell M (2007). The MAPKERK-1,2 pathway integrates distinct and antagonistic signals from TGFa and FGF7 in morphogenesis of mouse mammary epithelium. Dev. Biol. 309(1):193-207. PMID:17448457
Gear R, Yan M, Schneider J, Succoop P, Heffelfinger S, Clegg D (2007). Charles River Sprague Dawley rats lack early age-dependent succeptibility to DMBA-induced mammary carcinogenesis. Int J Biol Sci 3(7):408-416.
Jenkins S, Rowell C, Wang J, Lamartiniere C (2007). Prenatal TCDD exposure predisposes for mammary cancer in rats. Reproductive Toxicology 23:391-396. DOI:10.1016/j.reprotox.2006.10.004
Kariagina A, Aupperlee M, Haslam S (2007). Progesterone receptor isoforms and proliferation in the rat mammary gland during development. Endocrinology 148(6):2723-2736. DOI:10.1210/en.2006-1493 (show more/hide)
Progesterone (P), acting through progesterone receptor (PR) isoforms A and B, plays an important role in normal mammary gland development and is implicated in the etiology of breast cancer. Because of notable similarities between human and rat mammary gland development and hormonal responsiveness of mammary cancers in both the human and rat we undertook the analysis of progesterone action in the rat mammary gland. Using antibodies that detect only PRA or only PRB by immunohistochemistry, we investigated PRA and PRB expression at various mammary gland developmental stages (puberty, sexual maturity, pregnancy, lactation and after postlactational involution), and their functional roles in the regulation of proliferation. The percentage of PRA positive (PRA+) cells decreased from puberty to adulthood and further decreased after pregnancy, the percentage of PRB expressing cells was relatively constant at all developmental stages. Interestingly, during all developmental stages there was a significant proportion of cells that expressed only PRB. We found that the majority of PRA+ cells co-expressed PRB. In the pubertal and adult virgin mammary gland, PRA+PRB+ cells also expressed nuclear cyclin D1, protein that is essential for proliferation, but these cells did not contain the proliferation marker BrdU. Additionally, we found that PRA+PRB+ cells in the adult gland lacked expression of phospho-Rb, another protein required for proliferation, but expressed high levels of CDK inhibitors, p21 and p27 that capable of halting the cell proliferation. From these observations we conclude that it is likely that PRA+ PRB+ cells are cell cycle arrested and do not proliferate. These results imply that if P acts to promote proliferation in the virgin gland through its action in PRA+PRB+ cells it most likely does so through a paracrine mechanism(s). At various developmental stages, especially during pregnancy, a high percentage of cells that expressed only PRB were positive for BrdU. From this observation, we conclude these cells proliferate and that P acting through PRB may directly stimulate proliferation. Our study demonstrates that the rat mammary gland can be a superb animal model to study P action because, similarly to the adult human breast, it expresses PRB and both PRA and PRB are highly co-expressed in the same cell.
Lum DH, Tan J, Rosen S, Werb Z. (2007) Gene trap disruption of the mouse heparan sulfate 6-O-endosulfatase gene, Sulf2. Mol. Cell. Biol. 27:678-688 PMID:17116694
Moral R, Wang R, Russo I, Mailo D, Balogh G, Lamartiniere C, Russo J (2007). The plasticizer butyl benzyl phthalate induces genomic changes inn rat mammary gland after neonatal/prepubertal exposure. BMC Genomics 8:453 doi:10.1186/1471-2164-8-453
Oketch-Rabah HA, Barcellos-Hoff M (2007). Stroma, microenvironment and radiation carcinogenesis.. Reviews Cancer Biology & Therapeutics VNUN Kasid, A Haimovitz-Friedman & M Bar-Eli, editor. Transworld Research Network, Kerala, India. (show more/hide)
For many years, the areas surrounding cancerous cell growth have largely been ignored, while the cancer cells have received all the research attention. Recent work, however, demonstrates that the type of tissue surrounding tumors makes a big difference in regards to how fast or slow a cancer grows.
Radiation exposure is known to disrupt normal breast tissue. Changes in this tissue may ultimately increase the rate of tumor progression. To perform their studies, members of the Bay-area research team used ionizing radiation to change the tissue environment in normal breast cells and caused tumors to grow faster. This experiment first proves that disrupting normal tissue promotes cancer progression to a tumor, and second that ionizing radiation is capable of disrupting that tissue. In the future it is possible that cancer cells may be controlled by monitoring the tissue in their immediate environment.
Page-McCaw A, Ewald A, Werb Z (2007). Matrix metalloproteinases and the regulation of tissue remodeling. Nat. Rev. Mol. Cell Biol. 8:221-233. PMID:17318226
Wolff MS, Teitelbaum S, Windham G, Pinney S, Britton J, Chelimo C, Godbold J, Biro F, Kushi L, Pfeiffer C, Calafat A (2007). Pilot study of urinary biomarkers of phytoestrogens, phthalates, and phenols in girls. Env Hlth Perspective 115(1):116-21. DOI:10.1289/ehp.9488
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Aupperlee MD, Kariagina A, Osuch J, Haslam S (2006). Progestins and breast cancer. Breast Disease 24:38-58.
Biro FM, Khoury P, Morrison J (2006). Influence of obesity on timing of puberty. Int J Androl 29:272-277. DOI:10.1111/j.1365-2605.2005.00602.x
Claudio L (2006). Making progress on breast cancer. Env Hlth Perspective 114(2):A98-99.
Claudio L (2006). RTP leaders unite to advance environmental health. Env Hlth Perspective 114(9):A524-525.
Clegg DJ, Heffelfinger S (2006). Obesity: its influence on breast cancer susceptibility. Women's Health 2:1-9.
Fernandez-Gonzalez R, Munoz-Barrutia A, Barcellos-Hoff M, Ortiz de Solorzano C (2006). Quantitative in vivo microscopy: the return from the 'omics'. Curr Opin Biotechnol Oct 17(5):501-510. PMID:16899361
Fleisch MC, Maxwell C, Barcellos-Hoff M (2006). The pleiotropic roles of transforming growth factor beta in homeostasis and carcinogenesis of endocrine organs. Endocr Rel Cancer
13:379-400. (show more/hide
) (PDF summary
Transforming Growth Factor β (TGFβ) is an abundant signaling molecule which plays an important role in cellular regulation. TGFβ acts a both a tumor suppressor and a tumor promoter, making it a very complicated molecule to study.
The Bay-area research team discusses how TGFβ coordinates gene expression. They review the literature that during the beginning stages of cancer growth, TGFβ acts as a suppressor by stabilizing the chromosomes, while during the later stages of cancer growth TGFβ increases the rate of cancer cell invasion and migration. If TGFβ holds any therapeutic potential, more research is necessary to understand how the timing of these contradictory effects are controlled.
Glass RI , Bridbord K, Rosenthal J, Claudio L (2006). Global perspective on environmental health. Env Hlth Perspective 114(8):A454-455.
Haslam SZ (2006). Experimental mouse model of hormonal therapy effects on the postmenopausal breast. Breast Disease 24:71-78.
Heffelfinger SC. (2006) Breast Cancer. In Molecular carcinogenesis and the molecular biology of human cancer, Warshawsky D, Landolph Jr JR, eds., CRC press, Boca Raton, FL, CRC Press, 341-362
Kouros-Mehr H, Slorach E, Sternlicht M, Werb Z (2006). GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell
127:1041-1055. (article: doi:10.1016/j.cell.2006.09.048
PMID:17129787 (show more/hide
During development particular cells are given specific jobs; this is known as differentiation. The undifferentiated cells of a given population tend to multiply very quickly and have a higher propensity toward becoming cancerous. GATA-3 is known to play a role in differentiation by transforming undifferentiated cells in breast ducts into mature cells. Relatively little is known about the differentiation process undergone by mammary epithelial cells (the principal cells implicated in breast cancer), but recent research has determined that GATA-3 is a significantly player.
Multiple studies have demonstrated that breast tumors with high GATA-3 expression have a good prognosis since the cells tend to be better differentiated. Breast cancers with low GATA-3 expression tend to be diffuse, metastatic, and have a worse prognosis than others. This research demonstrates that GATA-3 expression levels may serve as a reliable prognostics tool in the fight against breast cancer.
Kouros-Mehr H, Werb Z (2006). Candidate regulators of mammary branching morphogenesis identified by genome-wide transcript analysis. Dev Dyn 235:3404-3412. PMID:17039550
In young animals and girls, the mammary gland develops during puberty in a process known as branching morphogenesis. The tip of a growing mammary bud repeatedly divides to generate an extensively branched network of ducts. This group of researchers decided to try and identify the genes that control the branching process. Gene analysis studies were used to reveal that 1074 genes increased at the tip of the growing bud, 222 genes increased in the surrounding tissue environment, and 385 genes increased in both.
The identification strategy designed for use in this study was shown to accurately predict known markers of cancer prevalence, and was then used to confirm the expression of supplementary genes. The new method also had the ability to pinpoint where exactly in the mammary gland the genes were being expressed. Therapeutic action to stop cancer growth may be possible if misregulated genes can be identified.
Lu P, Sternlicht M, Werb Z (2006). Comparative mechanisms of branching morphogenesis in diverse systems. J Mamm. Gland Biol. Neoplasia 11:213-228. PMID:17120154 (show more/hide)
The process known as branching morphogenesis is a fundamental biological process involved in creating an extensively branched network of tubes in breast, lung, kidney and salivary gland in mammals, but also in organs in lower animals such as fruit flies. This review by a Bay Area research team compared the differences and similarities between branching in the mouse and fly. The team highlighted the importance of the tissue surrounding the regions of uncontrolled cancerous cell growth, and used a time-lapse microscopy technique to watch the ducts branch in real time. The group identified a molecule known as FGF (fibroblast growth factor) as a key modulator of developmental activity. Using original state-of-the-art microscopy techniques, the team discovered that nearly 18% of all branching events were trifurcations, meaning three ducts were made from one original duct, instead of just two.
Several other studies have determined that the same mechanisms which govern fly tracheal branching also control mammary branching. Due to the similarities between the two systems, animal models remain essential to the continued study of human breast cancer.
Sternlicht MD (2006). Key stages in mammary gland development: The cues that regulate ductal branching morphogenesis. Breast Cancer Res 8:201. DOI:10.1186/bcr1368 PMID:16524451 (show more/hide)
Mammary branching refers to the creation of an extensive network of milk-carrying ducts. The pattern and cycle of ductal branching has been shown to be regulated by hormonal control by altering the immediate cellular environment. Endocrine hormones circulate throughout the entire body and are known to initiating branching. Locally, cyclic ovarian hormones like estrogen and progesterone are responsible for remodeling the original branching patterns. Cellular communication between the two tissue types functions to define growth boundaries and allow for reorganization of ductal branches.
This article summarizes the hormones and regulators involved in branching morphogenesis, emphasizing the fact that more research needs to be performed in order to understand how these molecules interact to control such a complicated process.
Sternlicht MD, Kouros-Mehr H, Lu P, Werb Z (2006). Hormonal and local control of mammary branching morphogenesis. Differentiation 74:365-381. PMID:16916375 (show more/hide)
Mammary branching refers to the formation of an extensive network of milk carrying ducts in the breast of female mammals. During adulthood these branches are maintained while new branches continue to form. This paper compares the similarities between methods of branching in human, mouse, and fly models. Mouse and fly models are useful when doing research because mice have mammary glands like humans do, and flies have similar branching organs and a very short lifecycle. It is necessary to understand normal breast development so doctors and researchers can identify when things become abnormal.
Studies in all three models- humans, mice, and flies- show that hormones control proper tissue organization. Localized growth in certain areas is additionally regulated by small molecules which can either increase or decrease branching. The way in which a few of these small molecules work is well understood, while many other important molecules have yet to be identified. Some molecules specifically control making the ducts longer, while others are in charge of making sure the branches successfully split from the primary duct.
The goal over the next five years is to understand how the growing tissue cells communicate with the regulatory molecules and how disruption of this interaction can lead to varying diseased states like cancer.
Wallenstein S, Chan W, Wetmur J (2006). Comparison of statistical models for analyzing genotype, inferred haplotype and molecular haplotype data. Molec. Genet. Metab. 89(3):270-273.
Wolff MS (2006). Endocrine disruptors: Challenges for environmental research in the 21st century. Annals NY Acad Sci 1076:228-38.
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Atabai K, Fernandez-Gonzalez R, Huang X, Ueki A, Kline A, Li Y, Sadatmansoori S, Smith-Steinhart C, Zhu W, Pytela R, Werb Z, Sheppard D (2005). Mfge8 is critical for mammary gland remodeling during involution. Mol. Biol. Cell. 16:5528-5537. PMID:16195353 (show more/hide)
In Petri dish studies, a molecule known as Mfge8 has been shown to be an official garbage collector, responsible for clearing old and dead cells. In the developing mammary gland, Mfge8 molecules are critical because they are required to clear the spaces inside the new milk ducts. Without the orderly removal of the cellular waste by Mfge8, the tissue can become inflamed and prevent proper development.
The research team demonstrated that Mfge8 has the same job in a live animal as it does in a Petri dish. The team showed that mammary gland tissue reorganization was significantly delayed in mice without any Mfge8 due to an excess of uncleared cellular garbage.
Aupperlee MD, Smith K, Kariagina A, Haslam S (2005). Progesterone receptor isoforms A and B: Temporal and spatial differences in expression during murine mammary gland development. Endocrinology 146:3577-88. DOI:10.1210/en.2005-0346 (show more/hide)
Progesterone (P) is capable of inducing cell turnover in the mammary gland. P acts through binding to the progesterone receptor (PR), which exists as two isoforms, PRA and PRB, that have different functions. In this study we used sections of mammary gland tissue stained with antibodies specific for PRA or PRB to show that PRA and PRB expression in mammary epithelial cells is spatially and temporally separated during normal mammary gland development in the mouse. In the virgin mammary gland when ductal development occurs, PRA is the predominant PR isoform expressed. PRB was the predominant PR isoform expressed during the formation of alveoli in response to pregnancy, while PRA expression decreased during pregnancy. Both PRA and PRB were expressed together in only a small percentage of cells; usually, mouse mammary epithelial cells expressed either PRA only or PRB only. During pregnancy, PRB expressing cells proliferated, whereas PRA expressing cells did not. These results indicate that different actions of P are mediated in PRA positive versus PRB positive cells in vivo. The separation of PR isoform expression into different cells and different stages of development in the mouse mammary gland provides a unique opportunity to further examine the specific functions of PRA versus PRB in vivo.
Barcellos-Hoff MH (2005). Integrative radiation carcinogenesis: Interactions between cell and tissue responses to DNA damage. Sem. Cancer Biol
15:138-147. (show more/hide
) (PDF summary
A new model of cancer as “a phenomenon of tissues” rather than just abnormal single cells is proposed to much more accurately describe how cancer actually develops. To test the new model, this group of Bay-area researchers documented cancerous growth from mice both exposed and unexposed to radiation. The irradiated tissue became very disorganized and exhibited excess cellular growth, while unirradiated tissue was two to four times less likely to show abnormal growth.
The authors discuss the literature that shows that the dose of radiation, the intensity of the radiation, and the type of tissue being exposed all play a part in determining the lasting effect of exposure. Fortunately, preliminary reports reason that restoring the health of the tissue surrounding the cancer may prevent detrimental effects.
Barcellos-Hoff MH, Medina D (2005). New highlights on stroma-epithelial interactions in breast cancer. Breast Cancer Res 7:33-36. PMID:15642180 (show more/hide)
It has been repeatedly shown that the areas surrounding breast cancer growth are just as, if not more, important than the site of the cancer growth. This study concentrated on the ability of an abnormal cellular neighborhood to induce and support cancerous cell growth. Experiments in which supportive tissue was treated with a cancer causing agent showed that tumors actually developed in the adjacent cells not treated with the carcinogen!
The research team is studying how blocking an important receptor pocket on surrounding tissue can cause a dramatic increase in the number of cancerous cells. The team argues that monitoring the state of tissue surrounding cancerous cells can serve as an effective means of monitoring and predicting cancerous activity.
Barcellos-Hoff MH, Park C, Wright E (2005). Radiation and the microenvironment: Tumorigenesis and therapy. Nat Cancer Rev
5:867-875. PMID:16327765 (show more/hide
) (PDF summary
Ionizing Radiation (IR) acts as both a carcinogen and a therapeutic agent. Low dose exposure can increase an individual’s risk of developing cancer, while high dose exposure is capable of slowing or stopping cancer growth. Radiation is known to damage the mammary tissue in two ways: directly and indirectly. IR induced DNA damage can lead to cell death, which is thought to be the basis of its therapeutic effects. DNA damage can also lead to mutations, which contribute to cancer.
Various studies reveal that ionizing radiation also leads to rapid changes in extracellular signals produced of exposed tissue, indicating that IR action may be two-fold: through DNA damage and altered signaling. The authors postulate that these two effects interact both in the response to high dose radiotherapy and the increase cancer risk following low dose radiation exposures. With an enhanced awareness of the dual properties of radiation, it may be possible to further optimize radiotherapy and limit its detrimental effect on cancer risk.
Fernandez-Gonzalez R, Barcellos-Hoff M, Ortiz de Solorzano C (2005). A tool for the quantitative spatial analysis of complex cellular systems. IEEE Trans Image Process 14:1300-1313. PMID:16190466
Galvez MP, Forman J, Landrigan P (2005). Children's environmental health. In Environmental Health: From Local to Global Eds. Frumkin H.
Grimm SL, Contreras A, Barcellos-Hoff M, Rosen J (2005). Cell cycle defects contribute to a block in hormone-induced mammary gland proliferation in C/EBP beta-null mice. J Biol. Chem 280(43):36301-36309. PMID:16120603 (show more/hide)
It is recognized that mice lacking the gene regulator C/EBPβ (which makes a molecule that regulates the life cycle of cells) are ten times less responsive to pregnancy hormones than are mice with the receptor. Studies show that the growing mammary ducts of mice without the C/EBPβ regulator are unable to receive hormonal messages. The research team studying these mice found that those lacking the regulator were also deficient in regulator E, a molecule responsible for controlling cellular growth.
This discovery provides an understanding of how breast cancer disrupts the normal cell cycle and causes excessive, tumorigenic, cell growth. A better understanding of normal cell cycle regulation will be able to offer additional insight into the molecular methods used to prevent tumor growth. With such knowledge, physicians and researchers may be capable of recognizing when cancerous growth is likely to occur, and prevent it from occurring as a result.
Heissig B, Rafii S, Ohki Y, Sato Y, Rafael T, Zhu Z, Hicklin D, Ogawa H, Werb Z, Hattori K (2005). Low-dose irradiation promotes tissue revascularization through Kit-ligand mediated release of VEGF from mast cells and MMP-9-mediated progenitor cell mobilization. J Exp. Med.
202:739-750. PMID:16157686 (show more/hide
) (PDF summary
For tumors to grow and spread, a cancer cell must be able to generate new blood vessels in order to support its increasing size. Ionizing radiation is used therapeutically to treat breast cancer. However, ionizing radiation can cause growth of new blood vessels. Even though ionizing radiation has been shown to cause the growth of new blood vessels, how it does this is poorly understood.
Members of the Bay Area research team decided to conduct a series of experiments to figure out how radiation caused the growth of new blood vessels. They discovered that a specific type of cell, known as a mast cell (which usually is involved in allergic responses), was responsible for promoting the generation of new blood vessels. When the researchers added molecules that inactivated the mast cells, no new blood vessels grew. This finding is important because it reveals that mast cells may be required for significant tumor growth.
Hiatt RA (2005). The Breast Cancer and the Environment Research Centers. Essays on the future of environmental health research. Env Hlth Perspective 16-23. DOI:10.1289/ehp.7987
Rodier F, Kim S, Nijjar T, Yaswen P, Campisi J (2005). Cancer and aging: The importance of telomeres in genome maintenance. Int. J Biochem Cell Biol 37: 977-990. PMID:15743672 (show more/hide)
Cancer is a result of uncontrolled cell growth and a loss of cell-cycle control. It has long been known that telomeres, or specialized DNA segments, play a vital role in the prevention of unwanted chromosomal breakdown. When telomeres become damaged or do not work properly, any organism is at a much higher risk of developing cancer.
The research team studied three binding proteins known to be involved in the regulation of telomeres. They discovered that the cancerous cells were direct descendents of cells who had lost appropriate telomere function. The team hypothesizes that the main cause of telomere dysfunction is damage from oxidative free radicals, unstable molecules which can cause damage to the body.
Rowell C, Carpenter D, Lamartiniere C (2005). Chemoprevention of breast cancer, proteomic discovery of genistein action in the rat mammary gland. J Nutrition Sci 135:2953S-2959S.
Rowell C, Carpenter D, Lamartiniere C (2005). Modeling biological variability in 2-D gel proteomic carcinogenesis experiments. Journal of Proteome Research 4:1619-1627.
Sternlicht MD, Sunnarborg S, Kouros-Mehr H, Yu Y, Lee D, Werb Z (2005). Mammary ductal morphogenesis requires paracrine activation of stromal EGFR via ADAM17-dependent shedding of epithelial amphiregulin. Development 132:3923-3933. PMID:16079154 (show more/hide)
The genes that control growth of the breast cells during pubertal development are of great interest because the same genes may be appropriated during breast tumor growth. The major growth factor that targets the mammary epidermal growth factor receptor (EGFR), a key receptor in tumor progression, is a membrane protein called amphiregulin (AREG). To work to stimulate cell division the factor needs to be clipped to release it so it can reach EGFR on cells further away. Previous studies have reported impaired mammary development in mice lacking AREG and EGFR. A third molecule, ADAM17, is an enzyme that clips AREG and acts as a messenger between the two molecules. The research team studying mice lacking these factors looked at how the three above mentioned molecules regulate mammary growth and why they are important in breast development.
The team figured out that one type of tissue, the epithelial cells of the ducts, produces AREG and another type of tissue (the neighboring fibroblasts) with the proper receptors (EGFRs) responds to AREG. Before the second type of tissue can receive the AREG message, the third molecule (ADAM17) is required to remove it from the site where it was produced. ADAM17 acts like a pair of scissors that cuts and releases AREG from the layer of tissue where it is produced so it can move across to the layer where it can act. The team is continuing to investigate what initiates the production of AREG.
Wetmur JG, Kumar M, Zhang L, Palomeque C, Wallenstein S, Chen J (2005). Molecular haplotyping by linking emulsion PCR: Analysis of PON1 haplotypes and phenotypes. Nucleic Acids Res 33:2615-2619.
Wolff MS, Britton J, Russo J (2005). TCDD and Puberty in Girls. Env Hlth Perspective 113:A17.
Cases S, Zhou P, Schillingford J, Wiseman B, Fish J, Hennighausen L, Werb Z, Farese Jr R (2004). Development of the mammary gland requires DGAT1 expression in stromal and epithelial tissues. Development 131(13):3047-3055. PMID:15163627 (show more/hide)
Appropriate mammary gland development and production of milk fat is required for proper milk production. Lipids are the primary components of fat, and the team hypothesizes that lower lipid levels lead to ambiguous classification of mammary cells, consequently increasing the risk of developing breast cancer. It has been previously demonstrated that mice lacking an enzyme known as DGAT1, which is implicated in fat production, are unable to produce milk. The team studying DGAT1 deficient mice explain that mice without this enzyme have abnormal lipid levels in their supporting cells, which increases their risk of breast cancer.
DGAT1 expression is required in proper mammary gland development during pregnancy, ultimately in milk production. Breast tissue of mice without the DGAT1 enzyme develops improperly and may lead to abnormal cancerous growth.
Claudio L (2004). Translation: Breast Cancer Takes Center Stage. Env Hlth Perspective 112:A92-94. (article)