E-cadherin regulates female tumor aggressiveness by controlling estrogen-sensitivity [ChIP-seq]

Sex disparities in cancer have been documented, but understanding of the underlying mechanisms is still limited, restricting precision medicine and the discovery of new therapeutic options. By analyzing overall cancer frequency, we found that women, between puberty and menopause, are more prone to develop cancer than men. We identified the cell adhesion molecule, E-cadherin, as a central node of the estrogen response in multiple cancers. Using original mouse melanoma model, a cancer with a higher incidence of women than in men during this period, we identify a previously unknown estrogen-sensitizing signaling pathway linking E-cadherin to the Estrogen Receptor  and to the Gastrin Releasing Peptide Receptor (GRPR), promoting melanoma aggressiveness in female only. Inhibition of this axis through GRPR targeting suppress metastasis in mice, representing a very promising therapeutic approach. Our results demonstrate that E-cadherin prevents carcinoma sensitivity to estrogens and identify a new therapeutic avenue to treat women suffering from multiple E-cadherin-dependent cancers.