Parity-Mediated Mechanisms Contributing to Breast Cancer Risk and Resistance
Endocrine factors during pregnancy contribute to both breast cancer risk and resistance. It is well established that a full-term pregnancy early in reproductive life confers a lifetime reduction in risk for postmenopausal breast cancer. Conversely, a first-time pregnancy late in reproductive life increases the risk of postmenopausal breast cancer. Likewise, a late first pregnancy will also increase the risk for parity associated breast cancer (PABC). Because breast cancer cases are expected to increase due to the current trend of delayed childbirth in western populations, understanding the parity-associated mechanisms that influence risk is important for proposing chemo-preventive measures. Therefore, in collaboration with the Jerry lab, we explore the endocrine regulated mechanisms, induced by parity, that contribute to breast cancer risk and p53-mediated resistance.
Roles of Activin and TGFb in Pregnancy Associated Breast Cancer
The mammary gland is exposed to increased levels of two transforming growth factor-beta (TGFb) super family members, activin and TGFb, during pregnancy and involution, and these two cytokines may influence breast cancer risk. Both activin and TGFb bind to their respective receptors, yet share common signaling pathways to inhibit cell growth. However, divergence in signaling pathways exists because elevated levels of TGFb transforms epithelial cells, rendering them tumorigenic, while activin does not. Furthermore, while TGFb is implicated in PABC, activin may have a protective role, because women with pre-eclampsia and higher serum levels of activin have a two-fold decrease risk of PABC. To test this hypothesis, we use a transplantable mouse mammary epithelial cell line, in vivo and in vitro, to compare TGFb-mediated and activin-mediated signal pathways, cellular responses and potential to promote tumorigenesis.
The Role of Estrogen and the protective effect of parity
Our work in mouse models has found that early parity, or estrogen and progesterone-treatment to mimic parity, enhances p53-mediated apoptotic responses to genomic stress and reduces tumor incidence. Recently, we have established a human mammary tissue explant culture system to demonstrate that apoptotic responses are also enhanced in the mammary epithelium from parous women. Interestingly, additional estrogen exposure appears to negate this protective effect. Estrogen receptor ratios are also altered favorably by parity and in tumor resistant strains of mice. In humans, unfavorable estrogen receptor ratios correlate with malignant progression. Currently, we are using specific estrogen receptor agonists to determine how receptor ratios may influence the balance between cell proliferation and genomic surveillance to confer the protective effect of parity.
Jerry DJ, Makari-Judson G, Crisi GM, Dunphy KA. 2013. Pregnancy offers new insights into mechanisms of breast cancer risk and resistance. Breast Cancer Res 15(5):312.
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Dunphy KA, Schneyer AL, Hagen MJ, Jerry JD. 2011. The role of activin in mammary gland development and oncogenesis.. Journal of mammary gland biology and neoplasia. 16(2):117-26.
Nguyen DH, Oketch-Rabah HA, Illa-Bochaca I, Geyer FC, Reis-Filho JS, Mao J-H, Ravani SA, Zavadil J, Borowsky AD, Jerry JD et al.. 2011. Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type. Cancer cell. 19(5):640-51.
Dunphy KA, Schneyer AL, Hagen MJ, Jerry JD. 2011. The role of activin in mammary gland development and oncogenesis.. J Mammary Gland Biol Neoplasia. 16(2):117-26.PubMed Jerry JD, Dunphy KA, Hagen MJ. 2010. Estrogens, regulation of p53 and breast cancer risk: a balancing act. Cell Mol Life Sci. 67(7):1017-23.PubMed
Dunphy KA, Tao L, Jerry JD. 2010. Mammary epithelial transplant procedure.. Journal of visualized experiments : JoVE. (40)PubMed Google Scholar BibTex Tagged RIS RTF XMLJerry JD, Dunphy KA, Hagen MJ. 2010. Estrogens, regulation of p53 and breast cancer risk: a balancing act. Cellular and molecular life sciences : CMLS. 67(7):1017-23. Dunphy KA, Blackburn AC, Yan H, O'Connell LR, Jerry JD. 2008. Estrogen and progesterone induce persistent increases in p53-dependent apoptosis and suppress mammary tumors in BALB/c-Trp53+/- mice. Breast cancer research : BCR. 10(3):R43. Becker KA, Lu S, Dickinson ES, Dunphy KA, Mathews L, Schneider SS, Jerry JD. 2005. Estrogen and progesterone regulate radiation-induced p53 activity in mammary epithelium through TGF-beta-dependent pathways. Oncogene. 24(42):6345-53. Becker KA, Lu S, Dickinson ES, Dunphy KA, Mathews L, Schneider SS, Jerry JD. 2005. Estrogen and progesterone regulate radiation-induced p53 activity in mammary epithelium through TGF-beta-dependent pathways. Oncogene. 24(42):6345-53.