Biomarkers derived from CmP signal network in triple negative breast cancers

Abstract

Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related death in women, accounting for approximately 30% of all new cancer cases. The prognosis of breast cancer heavily depends on the stage of diagnosis, with early detection resulting in higher survival rates. Various risk factors, including family history, alcohol consumption and hormone exposure, contribute to breast cancer development. Triple-negative breast cancer (TNBC), characterized by the absence of certain receptors, is particularly aggressive and heterogeneous. Cerebral cavernous malformations (CCMs), abnormal dilations of small blood vessels in the brain, is contributed by mutated genes like CCM1, CCM2, and CCM3 through the perturbed formation of the CCM signaling complex (CSC). The CSC-non-classic membrane progesterone receptors (mPRs)-progesterone (PRG) (CmP)/CSC-mPRs-PRG-classic nuclear progesterone receptors (nPRs) (CmPn) signaling network, which integrates the CSC with mPRs and nPRs, plays a role in breast cancer tumorigenesis. Understanding these pathways can provide insights into potential treatments. This paper focuses on the emerging field of CmPn/CmP signal networks, which involve PRG, its receptors (nPRs and mPRs), and the CSC. These networks play a role in tumorigenesis, particularly in TNBCs. Aims to deliver a thorough examination of the CmP/CmPn pathways concerning TNBCs, this paper provides a comprehensive overview of these pathways, explores their applications and highlights their significance in the context of TNBCs.

Keywords: CCM signaling complex (CSC); CmP signal network; Triple-negative breast cancer (TNBC); histological/molecular/immune subtypes of TNBCs; prognostic biomarkers.

Figure 1

Schematic representation of binding interaction among CCM proteins within the CSC. Our current data suggests that CCM1 utilizes its pY to bind to CCM2 classic PTB. One of three CCM1 pY can also compete with the CCM3 (FAT-H) to bind to the aPTB of the CCM2, suggesting CCM2, as a scaffold protein, plays a central role in the CSC. CCM1: blue color; CCM2: light green color; CCM3: brown color. CCM, cerebral cavernous malformation; CSC, CCM signal complex; N, N-terminus; C, C-terminus; pY, NPXY motifs; PTB, phosphotyrosine binding domain; aPTB, atypical PTB domain; FAT-H, Focal Adhesion Targeting-Homology domain.

Figure 2

Schematic diagram of mPR-specific PRG actions (PRG + MIF) within CmPn signal network. Within the CmPn signaling network, the CSC plays a regulatory role in modulating the interactions of PRG between nPRs and mPRs. This feedback regulation within the network involves the CSC acting as a modulator, influencing the channeling of PRG between nPRs and mPRs. CCM, cerebral cavernous malformation; CSC, CCM signal complex; PRG, progesterone; MIF, mifepristone; nPR, classic nuclear progesterone receptor; mPR, non-classic membrane progesterone receptor; eNOS, endothelial nitric oxide synthase; MMP, matrix metalloproteinase; CmPn, CSC-mPRs-PRG-nPRs.

Figure 3

CmP signal network-based biomarker discovery and therapeutic application. The depicted model showcases our current comprehension of the CmPn/CmP signal network’s role in breast cancer tumorigenesis, emphasizing the importance of mPRs in facilitating the continued influence of progesterone on both genomic and non-genomic actions. Investigating this network further holds potential for discovering innovative therapeutic strategies and prognostic biomarkers that specifically target the CmP signaling pathways in TNBC. nPRs, classic nuclear progesterone receptors; CCM, cerebral cavernous malformation; CSC, CCM signal complex; PRG, progesterone; mPRs, non-classic membrane progesterone receptors; TNBC, triple-negative breast cancer; CmP, CSC-mPRs-PRG; CmPn, CSC-mPRs-PRG-nPRs.