WP1. ROLE OF LAMININ-BINDING INTEGRINS EXPRESSED IN THE LUMINAL COMPARTMENT IN MAMMARY MORPHOGENESIS AND DIFFERENTIATION
1. Transgenic mouse model
First, mice deficient for laminin-binding integrins specifically in the mammary luminal cells were generated; they are called mutant mice. The absence of laminin-binding integrins in the luminal compartment of pregnant and lactating mutant mice was verified.
2. Role in pregnancy
Compared to pregnant control mice, the lobulo-alveolar development was delayed in pregnant mutant mice. Consistently, the level of milk gene expression was decreased in mutant luminal cells. Similar results were obtained using the mammary organoid model, which corresponds to small pieces of mammary gland cultured in 3D in a reconstituted matrix.
3. Role in lactation
In early lactation, histology and milk gene expression in mutant glands were similar to the controls. However, later on, an accumulation of anomalies was observed: perturbed cell polarity and induction of cell death in mutant luminal cells.
WP2. ROLE OF LAMININ-BINDING INTEGRINS ON THE LUMINAL PROGENITOR FUNCTIONS
The stem cell capacity of mutant luminal progenitors was strongly reduced compared to control ones. In contrast, basal cells were not affected.
WP3. IMPACTS OF LAMININ-BINDING INTEGRINS ON MAMMARY TUMORIGENESIS
The lack of p53, a tumor suppressor gene, leads to the amplification of luminal progenitor cells. Interestingly, the lack of laminin-binding integrins conteracts this effect. Next, a model of basal-like mammary tumorigenesis induced by the loss of p53 and BRCA1 was employed. Tumors reached ethical size in 6 month-old mice and were found positive for several basal markers as in human basal-like cancer, indicating this is pertinent mouse model. Analysis of mammary tumorigenesis in mice deficient for laminin-binding integrins is still ongoing.
Altogether, these results indicate laminin-binding integrins are essential in mammary luminal cells to support lobulo-alveolar development and lactogenic differentiation during pregnancy. They participate in maintaining cell polarity and survival during lactation. Their absence perturbed luminal progenitor functions in both physiological and p53-deficient contexts. These results were presented in several international conferences as posters (European Network of Breast Development and Cancer labs; Gordon Conference on Mammary Gland Development) and oral communication (Annual Meeeting of the French Society for ECM Biology). A manuscript for publication is currently under preparation.
