Abstract
p130Cas adaptor protein regulates basic processes such as cell cycle control, survival and migration. p130Cas over-expression has been related to mammary gland transformation, however the in vivo consequences of p130Cas over-expression during mammary gland morphogenesis are not known. In ex vivo mammary explants from MMTV-p130Cas transgenic mice, we show that p130Cas impairs the functional interplay between Epidermal Growth Factor Receptor (EGFR) and Estrogen Receptor (ER) during mammary gland development. Indeed, we demonstrate that p130Cas over-expression upon the concomitant stimulation with EGF and estrogen (E2) severely impairs mammary morphogenesis giving rise to enlarged multicellular spherical structures with altered architecture and absence of the central lumen. These filled acinar structures are characterized by increased cell survival and proliferation and by a strong activation of Erk1/2 MAPKs and Akt. Interestingly, antagonizing the ER activity is sufficient to re-establish branching morphogenesis and normal Erk1/2 MAPK activity. Overall, these results indicate that high levels of p130Cas expression profoundly affect mammary morphogenesis by altering epithelial architecture, survival and unbalancing Erk1/2 MAPKs activation in response to growth factors and hormones. These results suggest that alteration of morphogenetic pathways due to p130Cas over-expression might prime mammary epithelium to tumorigenesis.
Highlights
We demonstrated that p130Cas overexpression in presence of the concomitant stimulation with estrogen and epidermal growth factor (EGF) leads to aberrant mammary morphogenesis with the appearance of multicellular spherical filled structures characterized by impaired cell architecture and increased survival
By taking advantage of mammary organoids, a physiologically relevant 3D model for studying mammary morphogenesis [22], we demonstrate the involvement of p130Cas in this process
Our results show that high levels of p130Cas expression during puberty enhances EGF-dependent mammary branching providing the first evidence of the involvement of this adaptor protein in this physiological process
Summary
P130Cas, originally identified as a highly phosphorylated protein in cells transformed by v-Src and v-Crk oncogenes, is a multifunctional adaptor protein required for embryonic development [1] and is characterized by structural motifs that enable interactions with a variety of signaling molecules. These multiprotein complexes sense and integrate signaling originating from several receptor systems [2]. We demonstrated that p130Cas overexpression in presence of the concomitant stimulation with estrogen and EGF leads to aberrant mammary morphogenesis with the appearance of multicellular spherical filled structures characterized by impaired cell architecture and increased survival. Our data indicate that during mammary morphogenesis, high levels of p130Cas expression can enforce EGFR/ER-induced proliferation and survival pathways that are hallmarks for cell transformation
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