CCM signaling complex (CSC) coupling both classic and non-classic progesterone receptor signaling

Excessive progesterone (PRG) may increase breast cancer risk under hormone therapy during postmenopause or hormonal contraception. As a sex steroid hormone, PRG exerts its cellular responses through signaling cascades involving classic (genomic), non-classic (non-genomic), or both combined responses by binding to either classic nuclear PRG receptors or non-classic membrane PRG receptors. Currently, the intricate balance and switch mechanisms between these two signaling cascades remain elusive. Three genes, KRIT1 (CCM1), MGC4607 (CCM2), and PDCD10 (CCM3), have been demonstrated to form a CCM signaling complex (CSC). In this report, we discover that the CSC plays an essential role in coupling both classic and non-classic PRG signaling pathways by mediating crosstalk between them. The coupled signaling pathways were detailed through high throughput omics.