Affiliations: [a] Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, TX, USA | [b] Department of Biological Sciences, University of Texas at El Paso, El Paso, TX, USA
Correspondence:
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Corresponding author: Jun Zhang, Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, 5001 El Paso Drive, El Paso, El Paso, TX 79905, USA. Tel.: +1 915 215 4197; E-mail: jun.zhang2000@gmail.com.
Note: [1] Authors contributed equally.
Abstract: Breast cancer is the most 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). 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) can exert 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 equally important in PRG-mediated signaling. 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. 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(+/-) status. 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 CCMs 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 systems biology and TNBC clinical data, which helped us understand key factors within the CmP network and identify 6 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.
Keywords: Triple negative breast cancers, African American women, classic nuclear progesterone receptors, non-classic membrane progesterone receptors, cytoplasmic-nuclear trafficking, biomarkers, cancer therapy, CCM signaling complex, tumorigenesis, progesterone, mifepristone
