Targeting GRPR for sex hormone-dependent cancer after loss of E-cadherin

Sex inequalities in cancer are well documented, but the current limited understanding is hindering advances in precision medicine and therapies¹. Consideration of ethnicity, age and sex is essential for the management of cancer patients because they underlie important differences in both incidence and response to treatment^2,3. Age-related hormone production, which is a consistent divergence between the sexes, is underestimated in cancers that are not recognized as being hormone dependent^4-6. Here, we show that premenopausal women have increased vulnerability to cancers, and we identify the cell-cell adhesion molecule E-cadherin as a crucial component in the oestrogen response in various cancers, including melanoma. In a mouse model of melanoma, we discovered an oestrogen-sensitizing pathway connecting E-cadherin, β-catenin, oestrogen receptor-α and GRPR that promotes melanoma aggressiveness in women. Inhibiting this pathway by targeting GRPR or oestrogen receptor-α reduces metastasis in mice, indicating its therapeutic potential. Our study introduces a concept linking hormone sensitivity and tumour phenotype in which hormones affect cell phenotype and aggressiveness. We have identified an integrated pro-tumour pathway in women and propose that targeting a G-protein-coupled receptor with drugs not commonly used for cancer treatment could be more effective in treating E-cadherin-dependent cancers in women. This study emphasizes the importance of sex-specific factors in cancer management and offers hope of improving outcomes in various cancers.