Somatic loss of p53 leads to stem/progenitor cell amplification in both mammary epithelial compartments, basal and luminal

Abstract

Mammary epithelium comprises a layer of luminal cells and a basal myoepithelial cell layer. Both mammary epithelial compartments, basal and luminal, contain stem and progenitor cells, but only basal cells are capable of gland regeneration upon transplantation. Aberrant expansion of stem/progenitor cell populations is considered to contribute to breast tumorigenesis. Germline deletions of p53 in humans and mice confer a predisposition to tumors, and stem cell frequency is abnormally high in the mammary epithelium of p53-deficient mice. However, it is unknown whether stem/progenitor cell amplification occurs in both, basal and luminal cell populations in p53-deficient mammary tissue. We used a conditional gene deletion approach to study the role of p53 in stem/progenitor cells residing in the mammary luminal and basal layers. Using twoand three-dimensional cell culture assays, we showed that p53 loss led to the expansion of clonogenic stem/progenitor cells in both mammary epithelial cell layers. Moreover, following p53 deletion, luminal and basal stem/progenitor cells acquired a capacity for unlimited propagation in mammosphere culture. Furthermore, limiting dilution and serial transplantation assays revealed amplification and enhanced self-renewal in the basal regenerating cell population of p53-deficient mammary epithelium. Our data suggest that the increase in stem/progenitor cell activity may be, at least, partially mediated by the Notch pathway. Taken together, these results strongly indicate that p53 restricts the propagation and self-renewal of stem/progenitor cells in both layers of the mammary epithelium providing further insight into the impact of p53 loss in breast cancerogenesis. STEM CELLS

Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors

“…Our results are consistent with those reported in the mammary gland and bladder in which the growth of p63+ cells is inhibited by Notch signaling (Bouras et al, 2008). Aberrant expansion of stem/ progenitor cell populations contribute to tumorigenesis (Chiche et al, 2013;Lim et al, 2009). Thus, failure of mechanisms that prevent abnormal expansion of p63+ basal cells in the airway epithelium could also play a role in lung cancer.…”

Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

“…Therefore, K5-driven Cre expression should lead to excision of the conditional floxed allele from the entire mammary epithelium, which is consistent with our LacZ reporter assays (Fig. S1 A and B) and those of others (30) who showed that LacZ is expressed in all basal cells and most luminal cells in the mammary epithelium. K5-Cre Tg/+ should therefore induce mammary tumors with both luminal and basal cell origins.…”

“…The two major subtypes we identified were luminal A and basal-like tumors, suggesting that transposon mutagenesis is occurring in all mammary epithelium cell populations. Consistent with this, studies in K5Cre transgenic mice have identified Cre activity in early mammary cell progenitors (30). K5Cre should therefore inactivate Pten and activate SB transposition in both luminal and basal cell progenitors and might explain the development of different breast cancer subtypes in our SB mouse model.…”

Mammary stem cells and the differentiation hierarchy: current status and perspectives

“…Other potential transcriptional regulators of MaSCs include the transcription factors Stat3, CCAAT/enhancer-binding protein-b, and c-myc, all of which affect mammary repopulating ability in vivo (LaMarca et al 2010;Staniszewska et al 2012;Moumen et al 2013). Conversely, the tumor suppressor p53 serves a critical role in restricting the renewal of MaSCs and regulating their asymmetric division (Cicalese et al 2009;Chiche et al 2013). …”