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

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.

CCM signaling complex (CSC) couples both classic and non-classic Progesterone receptor signaling

“…We further discovered that mPR-specific PRG actions (treatment with PRG and MIF, only targeting mPRs) result in disruption of the CSC, indicating that the CmPn signaling network relies on an intricate feedback system to balance multiple signaling pathways to maintain homeostasis. mPR-specific PRG actions has recently been validated in nPR(-) Triple Negative Breast Cancer cells (TNBC, which only express mPRs) and nPR(-) vascular endothelial cells [ 12 – 14 ]. Additionally, utilizing omic approaches, we have elucidated alterations in signaling mechanisms under mPR-specific PRG actions, or disrupted CSC conditions, affecting numerous essential signaling cascades, further solidifying the essential role of the CmPn network during breast cancer tumorigenesis.…”

mPR-Specific Actions Influence Maintenance of the Blood–Brain Barrier (BBB)

“…Furthermore, as an autosomal dominant disorder with incomplete penetrance, many CCM gene mutation carriers are commonly asymptomatic, but when symptoms occur, the disease has typically reached the stage of focal hemorrhage with irreversible brain damage, while the underlying “trigger” for this seemingly “random” occurrence of hemorrhagic CCMs remains elusive [ 5 ]. However, our recent reports revealed that the CSC modulates progesterone (PRG)-mediated actions between classic nuclear PRG receptors (nPRs) and nonclassic membrane PRG/progestin and adipoQ receptors (mPRs/PAQRs) within the CSC-mPRs-PRG-nPRs (CmPn) signaling network in two nPR(+) (T47D, MCF7) breast cancer cell lines, and within the CSC-mPRs-PRG (CmP) signaling network in two nPR(−) triple-negative breast cancer cells (TNBCs: MDA-MB-231, MDA-MB-468) [ 5 , 6 , 7 , 8 ], shedding light on this mystery. We discovered that a well-known progesterone blocker, mifepristone (MIF, a major contraception drug), inhibits PRG actions only via classic-PRG-receptors-mediated signaling (nPRs) in nPR(+) cells.…”

“…In contrast, MIF can also act as a PRG agonist alone, and when combined with PRG, sex steroid signaling via nonclassic PRG receptors (mPRs) is synergistically enhanced to form a feedback loop in an mPR-specific fashion (only through mPRs). In this feedback regulation network, the CSC stability is disrupted by the negative effects of mPR-specific actions (MIF alone or combined (PRG/MIF)) via mPRs signaling or the positive effects of nPRs-specific PRG actions (only through nPRs) through classic nPRs signaling [ 5 , 6 , 7 , 8 ]. Our discovery reveals that the balance between classic and nonclassic PRG signaling (nPRs/mPRs) impacts the CSC function, and identifies the CSC as an important mediator of nPRs and mPRs crosstalk in nPR(+) cells.…”

“…Our observations are further supported by a previous finding that PRG can act simultaneously on both nPRs and mPRs, and that activation of mPRs-mediated signaling can potentiate expression of the hormone-activated nPR-2 isoform [ 9 ]. All of these data demonstrated the importance of the CSC for coupling both nPRs and mPRs by mediating crosstalk between them, and elucidated that the CSC can be regulated by feedback mechanisms involving PRG and its receptors (nPRs/mPRs) [ 5 , 6 , 7 , 8 ]. Furthermore, accumulated evidence has demonstrated that excessive PRG exposure, such as patients under hormone therapy during menopause/post-menopause, or females taking hormonal contraceptives/experiencing pregnancy, may be at an increased risk for hemorrhagic events.…”

“…In contrast, MIF binds to mPRs allosterically with PRG, and works synergistically with PRG in mPR-mediated signaling as an agonist [ 6 ]. Therefore, we have defined the two-sex-steroids-combined treatment (MIF + PRG) as mPR-specific PRG actions [ 6 , 7 , 8 ]. Together, these results suggest that pregnancy-/contraceptive-associated increased levels of mPR-specific PRG actions lead to increased risks of hemorrhage in CCM patients.…”