EGF-mediated induction of Mcl-1 at the switch to lactation is essential for alveolar cell survival

Abstract

Expansion and remodelling of the mammary epithelium requires a tight balance between cellular proliferation, differentiation and death. To explore cell survival versus cell death decisions in this organ, we deleted the pro-survival gene Mcl-1 in the mammary epithelium. Mcl-1 was found to be essential at multiple developmental stages including morphogenesis in puberty and alveologenesis in pregnancy. Moreover, Mcl-1-deficient basal cells were virtually devoid of repopulating activity, suggesting that this gene is required for stem cell function. Profound upregulation of the Mcl-1 protein was evident in alveolar cells at the switch to lactation, and Mcl-1 deficiency impaired lactation. Interestingly, EGF was identified as one of the most highly upregulated genes on lactogenesis and inhibition of EGF or mTOR signalling markedly impaired lactation, with concomitant decreases in Mcl-1 and phosphorylated ribosomal protein S6. These data demonstrate that Mcl-1 is essential for mammopoiesis and identify EGF as a critical trigger of Mcl-1 translation to ensure survival of milk-producing alveolar cells.

microRNA-143/145 loss induces Ras signaling to promote aggressive Pten-deficient basal-like breast cancer

“…(c) Distinct mammary epithelial cell populations may express differing levels of miRs, and aggressive PDAs may originate from cells with intrinsically low miR-143/145 expression. Indeed, data mining of miR expression from Fu et al (64) suggests that miR-145 may be differentially expressed in basal versus luminal mouse mammary cell lineages. However, in preliminary analyses with mouse pten-deficient mammary epithelial cells, we observed no significant difference in miR-143 or miR-145 expression in FACS-purified basal, luminal, luminal progenitor, or mature luminal mammary epithelial cells.…”

Injury-induced actin cytoskeleton reorganization in podocytes revealed by super-resolution microscopy

“…It has been suggested that filamentous actin in the form of long, thick, contractile stress fibers may be an artifact of in vitro culture stimulated by the attachment of cells to rigid substrates, such as plastic or glass. However, there are a few examples of cells with prominent stress fibers in vivo, including cells involved in the closure of epithelial sheets during embryogenesis, myoepithelial cells in wounds (1,2) and in mammary glands (3), and endothelial cells of large blood vessels (4)(5)(6). A common feature is the high level of mechanical stress experienced by cells with stress fibers.…”

RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers

“…MMTV-Cre (A strain) mediates a high frequency of excision (>95%) in both basal and luminal cells 22,33 . Mammary tumors that arise in this model express abundant amounts of RANK and a lower amount of RANKL, whereas most tumors from Trp53 +/− mice did not (Fig.…”