Notch Signaling Regulates Mammary Stem Cell Function and Luminal Cell-Fate Commitment

Abstract

The recent identification of mouse mammary stem cells (MaSCs) and progenitor subpopulations has enhanced the prospect of investigating the genetic control of their lineage specification and differentiation. Here we have explored the role of the Notch pathway within the mammary epithelial hierarchy. We show that knockdown of the canonical Notch effector Cbf-1 in the MaSC-enriched population results in increased stem cell activity in vivo as well as the formation of aberrant end buds, implying a role for endogenous Notch signaling in restricting MaSC expansion. Conversely, Notch was found to be preferentially activated in the ductal luminal epithelium in vivo and promoted commitment of MaSCs exclusively along the luminal lineage. Notably, constitutive Notch signaling specifically targeted luminal progenitor cells for expansion, leading to hyperplasia and tumorigenesis. These findings reveal key roles for Notch signaling in MaSCs and luminal cell commitment and further suggest that inappropriate Notch activation promotes the self-renewal and transformation of luminal progenitor cells.

Gamma-secretase inhibitors target tumor-initiating cells in a mouse model of ERBB2 breast cancer

“…Recent findings reveal that luminal progenitor cells may be the cells of origin of the Neuinduced tumors in the Neu (N202) transgenic strain (Jeselsohn et al, 2010). The effect of MRK-003 on mammary epithelial progenitor cell and tumor cell differentiation is consistent with an effect on Notch signaling; numerous studies have demonstrated that this pathway commits normal human and mouse mammary epithelial progenitor cells to the luminal fate and suppresses their differentiation toward the myoepithelial lineage (Buono et al, 2006;Bouras et al, 2008;Raouf et al, 2008;Yalcin-Ozuysal et al, 2010).…”

EZH2 promotes a bi-lineage identity in basal-like breast cancer cells

“…Normal luminal progenitors typically form hollow acini in 3D (7); in contrast, cancer cells form colonies lacking organized structure (26), and expression of a single oncogene is often sufficient to disrupt lumen formation (27,28). We found that HCC70 and SUM149 cell populations seeded on Matrigel formed rounded colonies (filled spheres/acini) (Figure 4a and supplementary Figure 6).…”

From milk to malignancy: the role of mammary stem cells in development, pregnancy and breast cancer

“…Additionally, the Notch pathway has also been implicated in regulating MaSC fates. Multiple reports have shown that Notch pathway ligands are expressed in the MaSC compartment, while the Notch receptors are expressed in the downstream progenitor/luminal compartment [25,30]. Ablation of Notch signaling through a Cbf-1 knockdown led to an expansion of MaSC activity, while forced constitutively active Notch signaling reduced MaSC activity [30].…”