Molecular Mechanisms of Mammary Gland Development

Glukhova

Marina Glukhova Team Leader Tel:

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.

Figure 1: Organization of the mammary epithelial bilayer. Immunodetection of calponin (in red) and cytokeratin 8 (in green), specific markers of basal myoepithelial and luminal epithelial cells, respectively.
Figure 1: Organization of the mammary epithelial bilayer. Immunodetection of calponin (in red) and cytokeratin 8 (in green), specific markers of basal myoepithelial and luminal epithelial cells, respectively.

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).

 

 

Figure 2: Coupe d’un carcinome mammaire invasive développé dans une souris K5N-caténine. Immunomarquage de l’actine de muscle lisse (en rouge) et la cytokératine basale, K 5 (en vert),
Figure 2: A section through an invasive mammary carcinoma developed by a K5N-catenin mouse stained for smooth muscle actin (red) and basal keratin 5 (green).

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.

Key publications

Year of publication 2014

Amandine Di-Cicco, Valérie Petit, Aurélie Chiche, Laura Bresson, Mathilde Romagnoli, Véronique Orian-Rousseau, Maria dM Vivanco, Daniel Medina, Marisa M Faraldo, Marina A Glukhova, Marie-Ange Deugnier (2014 Dec 16)

Paracrine Met signaling triggers epithelial-mesenchymal transition in mammary luminal progenitors, affecting their fate.

eLife : DOI : 10.7554/eLife.06104

Year of publication 2013

Michael D Prater, Valérie Petit, I Alasdair Russell, Rajshekhar R Giraddi, Mona Shehata, Suraj Menon, Reiner Schulte, Ivo Kalajzic, Nicola Rath, Michael F Olson, Daniel Metzger, Marisa M Faraldo, Marie-Ange Deugnier, Marina A Glukhova, John Stingl (2013 Sep 23)

Mammary stem cells have myoepithelial cell properties.

Nature cell biology : 942-50, 1-7 : DOI : 10.1038/ncb3025
Mejdi Moumen, Aurélie Chiche, Charles Decraene, Valérie Petit, Alberto Gandarillas, Marie-Ange Deugnier, Marina A Glukhova, Marisa M Faraldo (2013 Jul 25)

Myc is required for β-catenin-mediated mammary stem cell amplification and tumorigenesis.

Molecular cancer : 132 : DOI : 10.1186/1476-4598-12-132
S Cagnet, M M Faraldo, M Kreft, A Sonnenberg, K Raymond, M A Glukhova (2013 Jun 25)

Signaling events mediated by α3β1 integrin are essential for mammary tumorigenesis.

Oncogene : 4286-95 : DOI : 10.1038/onc.2013.391

Year of publication 2012

Aurélie Chiche, Mejdi Moumen, Valérie Petit, Jos Jonkers, Daniel Medina, Marie-Ange Deugnier, Marisa M Faraldo, Marina A Glukhova (2012 Nov 15)

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

Stem cells (Dayton, Ohio) : 1857-67 : DOI : 10.1002/stem.1429

Year of publication 2010

Karine Raymond, Stéphanie Cagnet, Maaike Kreft, Hans Janssen, Arnoud Sonnenberg, Marina A Glukhova (2010 Oct 12)

Control of mammary myoepithelial cell contractile function by α3β1 integrin signalling.

The EMBO journal : 1896-906 : DOI : 10.1038/emboj.2011.113
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