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

Abstract

AbstractTriple-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.