Molecular Profiling of Human Mammary Gland Links Breast Cancer Risk to a p27+ Cell Population with Progenitor Characteristics

Abstract

SUMMARY Early full-term pregnancy is one of the most effective natural protections against breast cancer. To investigate this effect, we have characterized the global gene expression and epigenetic profiles of multiple cell types from normal breast tissue of nulliparous and parous women, and carriers of BRCA1 or BRCA2 mutations. We found significant differences in CD44+ progenitor cells, where the levels of many stem cell-related genes and pathways, including the cell cycle regulator p27, are lower in parous women without BRCA1/BRCA2 mutations. We also noted a significant reduction in the frequency of CD44+p27+ cells in parous women, and showed using explant cultures that parity-related signaling pathways play a role in regulating the number of p27+ cells and their proliferation. Our results suggest that pathways controlling p27+ mammary epithelial cells and the numbers of these cells relate to breast cancer risk, and can be explored for cancer risk assessment and prevention.

Bringing androgens up a NOTCH in breast cancer

“…Among the largest gene changes observed in virgin vs parous samples was downregulation of the luminal, HS-MEC-secreted factors WNT4 and AREG (Meier-Abt et al 2013). The relevance of HS-MECs in parity-induced breast cancer protection was validated in human breast tissue assessed for the greatest transcriptional and methylation changes after parity (Choudhury et al 2013). The latter study implicated a subset of HS-MECs expressing the cell cycle regulator P27 as a principal effector of the breast cancer protective effect of pregnancy.…”

“…Altogether, these studies point to HS-MECs exerting a powerful developmental influence on the normal MEC population. Accumulating evidence indicates that HS-MECs also influence breast cancer susceptibility (Choudhury et al 2013, Hodgson et al 2013, Meier-Abt et al 2013, Tarulli et al 2013, an effect that may extend to both ERa-positive and ERa-negative breast cancers, and supports the use of androgen modulation as a form of breast cancer therapy as it principally targets the HS-MEC population.…”

Establishment and Characterization of Vaginal Tissue Primary Culture: Feasibility of Cell Therapy for Mayer-Rokitansky-Kuster-Hauser Syndrome (MRKHS) Patient Treatment

“…Explants technique is a well-established methodology to obtain primary cell cultures [14][15][16]. We established vaginal cultures, which showed heterogeneous morphology.…”

Breast Cancer Prevention: Lessons to be Learned from Mechanisms of Early Pregnancy–Mediated Breast Cancer Protection

“…1C). Furthermore, parity in women induced a decrease in the number of mammary hormone-sensing (ER þ ) cells (4,22), an apparent reduction in Wnt 4 expression (as can be derived from the presented raw data), and a cellular proliferation block in the corresponding breast tissues (4). These similarities between mice and women regarding parity-induced cellular and molecular changes in mammary epithelium strongly indicate that decreased progesterone-and Wnt4-mediated Wnt signaling in mammary stem/progenitor cells plays a key role in the protective effect of early-age pregnancy against breast cancer.…”

“…To develop such pharmacologic prevention strategies against breast cancer, the cellular and molecular mechanisms underlying the protective effect of early-age pregnancy must be understood. In this regard, considerable progress has been made recently by the demonstration that early-age pregnancy changes cell fate determining signaling pathways preferentially in mammary stem/progenitor cells (3,4). Although several challenges remain before successful pharmacologic prevention against breast cancer can be achieved, the ultimate goal must be the translation of these underlying processes into methods to bring about the protective effect of pregnancy at early age in women without the need for teenage pregnancies.…”