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

Abstract 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. One Sentence Summary We discover a novel signaling network among the CCM signaling complex (CSC), classic and non-classic progesterone receptors, and their ligands-progesterone/mifepristone, is dynamically modulated and fine-tuned with a series of feedback regulations; perturbation of this intricate balance, such as hormone therapy in the postmenopause or hormonal contraception regimen, or perturbed CSC signaling could result in increased risks in breast cancer or compromising tumor therapy.