Our aim is to characterize the molecular mechanisms controlling the functions of stem and progenitor cells residing in mammary epithelial bilayer (Fig. 1) and analyze the contribution of these cells to tumorigenesis.
Characterisation of mammary stem and progenitor cells
In cooperation with John Stingl (Cambridge University, UK) we have demonstrated that mammary myoepithelial cells possess stem cell properties (Prater et al., 2014). Using an inducible lineage tracing approach we followed the progeny of myoepithelial cells and showed that, they function as long-lived lineage-restricted stem cells in the virgin state and during pregnancy.
We have identified a new surface marker for the enrichment of mouse mammary luminal progenitors, ICAM-1, and showed that paracrine activation of Met receptor stimulates the clonogenic activity of ICAM-1-expressing luminal progenitors, controlling their survival and proliferation, and promotes a luminal-to-basal switch while triggering EMT program (Di Cicco et al., 2015).
Contribution of stem cells to mammary tumorigenesis
The transgenic K5DNbcat mice generated by our team display a constitutive activation of Wnt/b-catenin signalling due to the expression of a stabilised form of b-catenin in the mammary basal cell layer and develop mammary lesions resembling metaplastic basal-like mammary carcinomas (Fig. 2.; Moument et al., 2013). Our results suggest that in this model, tumors may originate from basal-type stem cells. We have recently demonstrated that the proto-oncogene Myc is required for mammary stem cell self-renewal, whereas the tumor suppressor p53 restricts expansion of stem and progenitor cells in mammary basal and luminal compartments. Consistently with these data, we have found that Myc is required for the stem cell amplification leading to tumorigenesis, whereas p53 acts to retard tumor development in K5DNbcat mice (Moumen et al., 2013; Chiche et al., 2013).
Interactions between mammary epithelial cells and extracellular matrix
We have previously shown that b1 integrin deletion leading to lack of several integrin dimers in mammary basal cells causes a loss of functional stem cell population (Taddei et al., 2008). Our subsequent studies have implicated laminin-binding integrin a3b1 in the control of the activation of the FAK/Rac/PAK1 pathway and demonstrated, that this pathway is essential for normal contractile activity of mammary myoepithelial cells and for mammary tumorigenesis (Raymond et al., 2011; Cagnet et al., 2013). Our current work is focused on the analysis of the functions of laminin-binding integrins in the maintenance of the mammary stem and progenitor cell populations in basal and luminal compartments of the mammary epithelium.