Bhalli, M. | Search bioRxiv

bioRxiv2021

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

Triple-negative breast cancer (TNBC) constitutes [~]15 percent of all diagnosed invasive breast cancer cases with limited options for treatment since immunotherapies that target the ER, PR and HER2 receptors are ineffective. Progesterone (PRG) is capable of inducing its effects through either classic, non-classic, or combined responses by binding to classic nuclear PRG receptors (nPRs) or non-classic membrane PRG receptors (mPRs). Under PRG-induced actions, we previously demonstrated that the CSC (CCM signaling complex) can couple both nPRs and mPRs into a CmPn signaling network which plays an important role in nPR(+) breast cancer tumorigeneses. We recently defined the novel CmP signaling network in TNBC cells, which overlapped with our previously defined CmPn network in nPR(+) breast cancer cells. In this study, we were able to demonstrate alterations to key tumorigenesis pathways in Caucasian American Women (CAW)-TNBC cells, under mPRs-specific steroid actions. These results suggest that even though TNBC diagnoses in AAW are associated with more aggressive forms of the disease, and experience a higher mortality rate, TNBC in CAW share similar altered signaling pathways, under mPRs-specific steroid actions, demonstrating the overall aggressive nature of TNBCs, regardless of racial differences. Furthermore, in this report, we have identified 21 new CAW-TNBC specific candidate biomarkers that reinforce the definitive role of the CmP signaling network in TNBC tumorigenesis, initially identified in our previous studies with AAW-TNBCs. This new set of potential prognostic biomarkers may revolutionize molecular mechanisms and currently known concepts of tumorigenesis in CAW-TNBCs, leading to hopeful new therapeutic strategies.

cancer biology↗

bioRxiv2021

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

Breast cancer is the most commonly diagnosed cancer worldwide and remains the second leading cause of cancer death. While breast cancer mortality has steadily declined over the past decades through medical advances, an alarming disparity in breast cancer mortality has emerged between African American women (AAW) and Caucasian American women (CAW); and new evidence suggests more aggressive behavior of triple-negative breast cancer (TNBC) in AAW may contribute to racial differences in tumor biology and mortality. Progesterone (PRG) is capable of exerting its cellular effects through either its classic, non-classic or combined responses through binding to either classic nuclear PRG receptors (nPRs) or non-classic membrane PRG receptors (mPRs), warranting both pathways an equally important status in PRG-mediated signaling. In our previous report, we demonstrated that the CCM signaling complex (CSC) consisting of CCM1, CCM2, and CCM3 proteins can couple both nPRs and mPRs signaling cascades to form a CSC-mPRs-PRG-nPRs (CmPn) signaling network in nPR positive(+) breast cancer cells. In this report, we furthered our research by establishing the CSC-mPRs-PRG (CmP) signaling network in nPR(-) breast cancer cells, demonstrating that a common core mechanism exists, regardless of nPR(+/-) cell type. This is the first report stating that inducible expression patterns exist between CCMs and major mPRs in TNBC cells. Furthermore, we firstly show mPRs in TNBC cells are localized in the nucleus and participate in nucleocytoplasmic shuttling in a coordinately synchronized fashion with CCM proteins under steroid actions, following the same cellular distribution as other well-defined steroid hormone receptors. Finally, for the first time, we deconvoluted the CmP signalosome by using multi-omics approaches, which helped us understand key factors within the CmP network, and identify 21 specific biomarkers with potential clinical applications associated with AAW-TNBC tumorigenesis. These novel biomarkers could have immediate clinical implications to dramatically improve health disparities among AAW-TNBCs.

cancer biology↗