Haley Griffin

 Introduction: Breast cancer is the predominant cancer and second cause of death due to women. The mammary epithelium undergoes extensive changes throughout a women’s life, and these developmental alterations are associated with progesterone and estrogen. As a result, ER+/PR+ subtype breast cancers are especially linked to reproductive risk factors. The Wnt signaling cascade is essential for the regulation of mammary epithelium stem cells throughout life, specifically its interaction with progesterone during pregnancy. With early pregnancy, there is both a reduction in progesterone-receptor positive luminal epithelial cells and a downregulation of the Wnt signaling pathway. These alterations provide a lifelong protective mechanism against breast cancer, which could be useful in providing protective treatment in the future. Methods: In Arendt et al., human mammary epithelial cells (MEC) were isolated and treated with lentivirus to stimulate overexpression of Wnt. Characterized assays were used to analyze progenitor activity in response to estrogen and progesterone. Meier et al.’s work isolated MEC subtypes via flow cytometry in both parous and virgin mice of equal age. Immunohistochemistry was used to analyze Wnt target gene expression and PR positive cells. PTEN knockout mice were used to confirm tumor promoting role of Wnt signaling in breast cancer. Muenst et al. reconfirmed previous studies in human populations via immunohistochemistry tests for Wnt4 and progesterone receptor sensitive epithelial cells on MEC samples from 125 women (mixture of early parous, late parous, and virgin patients). Results: Ardent et al. shows that both ER/PR hormones regulate MEC growth, with progesterone specifically stimulating ductal progenitor cell differentiation. Meier et al. found that parous mice had a decrease in Wnt signaling in progenitor cells which corresponded to a decrease in progesterone receptor positive cells. This change was not observed in mice with late pregnancies. Muenst et al. reconfirmed results of mice studies in the human analysis, showing that early pregnancy resulted in lower Wnt4 expression and PR sensitive epithelial cells compared to nulliparous women. Conclusion: Wnt4 is secreted by luminal cells in response to progesterone acting on luminal hormone-sensing cells. Wnt4 then binds to basal cells (which possess stem and progenitor cell properties) thus activating the  Wnt cell proliferation signaling cascade. In early pregnancy, there is a reduction of PR positive cells and Wnt4- secreting luminal cells, resulting in a decrease of Wnt signaling and thus basal mammary progenitor cell  activity. These changes result in a protective mechanism against future breast cancer.

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