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

This is the authors' abstract. We don't add key points for this paper.

Background: Breast cancer, the most commonly diagnosed cancer, remains the second leading cause of cancer death in the United States, and excessive Progesterone (PRG) or Mifepristone (MIF) exposure, including females under Hormone Replacement Therapy or taking hormonal contraceptives during their reproductive ages, may be at an increased risk for developing breast cancer. PRG exerts its cellular responses through signaling cascades involving classic, non-classic, or combined responses by binding to either classic nuclear PRG receptors (nPRs) or non-classic membrane PRG receptors (mPRs). Currently, the intricate balance and switch mechanisms between these two signaling cascades remain elusive. Three genes, CCM1-3, form the CCM signaling complex (CSC) which mediates multiple signaling cascades. Methods: Utilizing molecular cellular biology, Omics, and systems biology approaches, we analyzed the relationship among CSC, PRG, and nPRs/mPRs. Results: We discover that the CSC plays an essential role in coupling both classic and non-classic PRG signaling pathways by mediating crosstalk between them, forming the CmPn (CSC-mPRs-PRG-nPRs) signaling network. We found that mPR-specific PRG actions (PRG+Mifepristone) play an essential role in this CmPn network during breast cancer tumorigenesis; identified 4 categories of candidate biomarkers (9 intrinsic, 2 PRG-inducible, 1 PRG-repressive, 1 mPR-specific PRG-repressive, and 2 mPR-responsive) for Luminal-A breast cancers during tumorigenesis; and confirmed prognostic application of RPL13 and RPL38 as intrinsic biomarkers in Luminal-A breast cancers using a dual validation method. Conclusions: We discover that the CSC plays an essential role in the CmPn signaling network.