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.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 (1).It has been well-defined that PRG commonly binds to its nuclear receptor (PR) as transcriptional factors in classic genomic actions (2). PR has two major isoforms (PR1/2) which are alternative transcripts with quite different cellular functions (2). PRG can evoke both genomic and non-genomic actions of the classical PR1/2. In non-genomic responses, PRG binds PR1/2, leading to rapid changes in intracellular calcium/chloride levels in a rapid non-classical mechanism (3), which is defined as membrane-initiated (non-genomic) actions. Recently, two new groups of membrane-bound PRG receptors which are unrelated to PR1/2 have been identified: 1). 5 members of membrane progestin receptors (mPRs)/the Class II progestin and adipoQ receptor (PAQRs); 2). 4 members of the b5-like heme/steroid-binding protein family known as sigma2 receptor (S2R)/progesterone receptor membrane components (PGRMCs) (4, 5).It has been shown that mPRs are highly expressed in reproductive tissues and function by coupling to G proteins (6) to execute their rapid non-classical actions. Homozygous mutant fish of all mPR genes were generated with no phenotype, suggesting redundancy shared by mPR genes (7). Three CCM genes, KRIT1 (CCM1), MGC4607 (CCM2), and PDCD10 (CCM3), form the CCM signaling complex (CSC) that mediates multiple si...

CmP signaling network unveils novel biomarkers for triple negative breast cancer in African American women

“…Our discovery that mPRß is predominantly a nuclear protein and capable of shuttling between the nucleus and cytosol under steroid actions suggests that mPRs are a new type of PRG receptors, behaving the same as classic nPRs that can perform both genomic and non-genomic PRG-mediated actions. Based on these novel findings, we provide proof of principle that the CmP signaling network is a core component of our previously defined CmPn signaling network (Abou-Fadel et al, 2020b). To emphasize one of the most exciting findings in this study, utilizing comprehensive omic approaches, we identified a total of 21 AAW-TNBC specific biomarkers (Table 1) associated with tumorigenesis of AAW-derived TNBC cells.…”

“…In our previous report, we demonstrated that the CCM signaling complex (CSC) consisting of CCM1, CCM2, and CCM3 can couple both nPRs and mPRs signaling cascades to form a CSC-mPRs-PRG-nPRs (CmPn) signaling network in nPR positive(+) breast cancer cells (Abou-Fadel et al, 2020b). Our previous data support that the CSC plays an important role during breast cancer tumorigenesis by coupling classic nPRs and non-classic mPRs (PAQRs) under PRG-induced actions (Abou-Fadel et al, 2020b). Among TNBCs, over 70% of TNBCs are basal phenotype breast cancers (BPBC), one of the most aggressive TNBC cancers; mPRs role in tumorigenesis of BPBC is of great interest since BPBC derived cells do not express nPRs (Zuo et al, 2010).…”

Disrupting the CmP signaling network unveils novel biomarkers for triple negative breast cancer in Caucasian American women

“…The existence of the PRG-mPRs signaling cascade in nPR(+/-) cells have been well documented [30, 33, 51–53], demonstrating that PRG signaling in nPR(-) cell lines is solely mediated through mPRs (PAQRs) [30]. In our previous study, we defined the novel CmP signaling network in TNBC cells [31], which overlapped with our previously defined CmPn network in nPR(+) breast cancer cells [25], and observed that combined steroid actions have a positive effect on CSC protein expression in TNBCs with inducible patterns of expression in AAW-TNBC cells [31]. Using extensive multi-omics approaches, we were once again able to demonstrate alterations to key tumorigenesis pathways including cytokine-mediated responses, Wnt, Integrin, GnRH, and angiogenesis signaling pathways in CAW-TNBC cells under mPRs-specific steroid actions, which were in parallel to the observation in AAW-TNBC cells under identical conditions [31].…”

“…Progesterone (PRG), a sex steroid hormone, is capable of inducing its effects through either classic, non-classic, or combined responses by binding to either classic nuclear PRG receptors (nPRs) or non-classic membrane PRG receptors (mPRs). Under PRG-induced actions, it has been found that the CSC (CCM signaling complex), composed of CCM1, CCM2, and CCM3, can couple both nPRs and mPRs into a CSC-mPRs-PRG-nPRs (CmPn) signaling network which plays an important role in breast cancer tumorigeneses [25]. Mifepristone (MIF), an nPR antagonist and mPR agonist, has been shown to suppress basal TNBC stem cells [26].…”

“…Mifepristone (MIF), an nPR antagonist and mPR agonist, has been shown to suppress basal TNBC stem cells [26]. Our previous data show that combined actions (MIF+PRG) is mPR specific, and work synergistically towards mPRs [25]. Furthermore, several reports have demonstrated that elevated levels of MIF can enhance growth inhibition and induction of apoptosis in the presence of high dose progesterone in either nPR(+/-) subtypes, and is also able to inhibit the growth of nPR(-) MB231 (TNBC-Caucasian American Women) cells [27–29].…”