The concept of stem cell in the mammary gland and its implication in morphogenesis, cancer and prevention

Abstract

The breast attains its maximum development during pregnancy and lactation. After menopause the breast regresses in both nulliparous and parous women containing lobular structures that have been designated lobules type 1. Despite the similarity in the lobular composition of the breast at menopause, the fact that nulliparous women are at higher risk of developing breast cancer than parous women, indicates that Lobules type 1 in these two groups of women might be biologically different, or exhibit different susceptibility to carcinogenesis. Based on these observations it was postulated that the Lobule type 1 found in the breast of nulliparous women and of parous women with breast cancer never went through the process of differentiation, retaining a high concentration of epithelial cells that are targets for carcinogens and therefore susceptible to undergo neoplastic transformation, these cell are called Stem cells 1, whereas Lobules type 1 structures found in the breast of early parous postmenopausal women free of mammary pathology, on the other hand, are composed of an epithelial cell population that is refractory to transformation called Stem cells 2. It was further postulated that the degree of differentiation acquired through early pregnancy has changed the "genomic signature" that differentiates the Lobule type 1 from the early parous women from that of the nulliparous women by shifting the Stem cell 1 to a Stem cell 2 that is refractory to carcinogenesis, making this the postulated mechanism of protection conferred by early full term pregnancy. The identification of a putative breast stem cell (Stem cell 1) has reached in the last decade a significant impulse and several markers also reported for other tissues have been found in the mammary epithelial cells of both rodents and humans. Although still more work needs to be done in order to better understand the role of the Stem cell 2 and its interaction with the genes that confer it a specific signature, collectively, the data presently available provides evidence that pregnancy, through the process of cell differentiation, shifts the Stem cell 1 to Stem cell 2, cells that exhibit a specific genomic signature that could be responsible for the refractoriness of the mammary gland to carcinogenesis.

Full-term Pregnancy Induces a Specific Genomic Signature in the Human Breast

“…Nevertheless, the final molecular mechanisms by which these transcription factors regulate the differentiation of the parous breast epithelium need further investigation. Transcription factors also associated to coactivators and chromatin remodeling, such PCAF, which have previously found to be significantly up-regulated in breast epithelial cells of parous women (6,(25)(26)(27), seem to play Figure 1. Unsupervised hierarchical clustering analysis using the expression profiles of 2,541 globally varying genes across the nulliparous and parous data sets representing parous controls ( ), parous cases ( ), nulliparous controls ( ), and nulliparous cases ( ).…”

“…Other studies have reported that additional pregnancies and breast-feeding confer greater protection to young women, including a statistically significantly reduced risk of breast cancer in women with deleterious BRCA1 mutations who breast-fed for a cumulative total of >1 year (3,4). Our studies, designed for unraveling what specific phenomena occurred in the breast during pregnancy for conferring a lifetime protection from developing cancer, led us to the discovery that endogenous endocrinological or environmental influences affecting breast development before the first full-term pregnancy were important modulators of the susceptibility of the breast to undergo neoplastic transformation (5,6). The fact that exposure of the breast of young nulliparous females to environmental physical agents (7) or chemical toxicants (8,9) results in a greater rate of cell transformation indicates that the immature breast possesses a greater number of susceptible cells that can become the site of origin of cancer, similarly to what has been reported in experimental animal models (5,6,10,11).…”

“…Our studies, designed for unraveling what specific phenomena occurred in the breast during pregnancy for conferring a lifetime protection from developing cancer, led us to the discovery that endogenous endocrinological or environmental influences affecting breast development before the first full-term pregnancy were important modulators of the susceptibility of the breast to undergo neoplastic transformation (5,6). The fact that exposure of the breast of young nulliparous females to environmental physical agents (7) or chemical toxicants (8,9) results in a greater rate of cell transformation indicates that the immature breast possesses a greater number of susceptible cells that can become the site of origin of cancer, similarly to what has been reported in experimental animal models (5,6,10,11). In these models, the initiation of cancer is prevented by the differentiation of the mammary gland induced by pregnancy (11,12).…”

“…Work reported here was designed with the purpose of testing whether a similar phenomenon occurs in the atrophic breast of postmenopausal parous women, specifically in the epithelium of lobule type 1 (Lob 1), the site of origin of breast carcinomas (5,6). Our results support our hypothesis that parous women that had not developed breast cancer after menopause exhibit a genomic ''signature'' that differs from that present in the breast of parous postmenopausal women with cancer or in nulliparous women who traditionally represent a high breast cancer risk group (1-6).…”

Estrogen-Induced Depurination of DNA: A Novel Target for Breast Cancer Prevention

“…These cells were injected in SCID mice for assay of tumorigenicity. Only E 2 -70-C3 and E 2 -70-C5 were tumorigenic in 2/12 and 9/10 animals injected, respectively [99]. The tumors were poorly differentiated adenocarcinomas, ER-α, ER-β and progesterone receptor negative, expressing immunocytochemically high molecular weight basic keratin (+++), E Cadherin (+) and CAM5.2 (+).…”