Membrane Progesterone Receptors (mPRs/PAQRs) Are Going beyond Its Initial Definitions

Aickareth, Justin; Hawwar, Majd; Gnanasekaran, Revathi; Zhang, Jun

doi:10.3390/membranes13030260

Cited by 10 publications

(11 citation statements)

References 162 publications

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“…It has been defined that the three CCM proteins form the CCM signaling complex (CSC) that couples classic and non-classic progesterone (PRG) receptors (nPRs/mPRs) to form the CSC-mPR-PRG-nPR (CmPn) signaling network, which has a major impact on angiogenesis and tumorigenesis [150][151][152][153][154][155][156][157]. Key members of the CmPn network have been defined as important biomarkers for certain oncogenic conditions [150][151][152]155,156,[158][159][160][161][162]. Since most common GOF PIK3CA mutations (hotspots) in breast cancers are somatic point mutations, by utilizing the GDC data portal from the National Cancer Institute (NCI), simple somatic mutations (SSM) of breast cancer lesions for TP53 and PIK3CA genes, along with all key CmPn signaling components, were assessed with Oncogrid.…”

Section: Somatic Gof Pik3ca Mutations Are Oncogenic and Driver In Bre...mentioning

confidence: 99%

Familial CCM Genes Might Not Be Main Drivers for Pathogenesis of Sporadic CCMs-Genetic Similarity between Cancers and Vascular Malformations

Zhang

Croft

2023

JPM

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Cerebral cavernous malformations (CCMs) are abnormally dilated intracranial capillaries that form cerebrovascular lesions with a high risk of hemorrhagic stroke. Recently, several somatic “activating” gain-of-function (GOF) point mutations in PIK3CA (phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit p110α) were discovered as a dominant mutation in the lesions of sporadic forms of cerebral cavernous malformation (sCCM), raising the possibility that CCMs, like other types of vascular malformations, fall in the PIK3CA-related overgrowth spectrum (PROS). However, this possibility has been challenged with different interpretations. In this review, we will continue our efforts to expound the phenomenon of the coexistence of gain-of-function (GOF) point mutations in the PIK3CA gene and loss-of-function (LOF) mutations in CCM genes in the CCM lesions of sCCM and try to delineate the relationship between mutagenic events with CCM lesions in a temporospatial manner. Since GOF PIK3CA point mutations have been well studied in reproductive cancers, especially breast cancer as a driver oncogene, we will perform a comparative meta-analysis for GOF PIK3CA point mutations in an attempt to demonstrate the genetic similarities shared by both cancers and vascular anomalies.

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Section: Somatic Gof Pik3ca Mutations Are Oncogenic and Driver In Bre...mentioning

confidence: 99%

Familial CCM Genes Might Not Be Main Drivers for Pathogenesis of Sporadic CCMs-Genetic Similarity between Cancers and Vascular Malformations

Zhang

Croft

2023

JPM

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“…This finding has led to the integration of these three “independent” signaling cascades, giving rise to the complexes referred to as CmPn signal network ( Figure 2 ) ( 33 - 36 ). This network is present in both nPR-positive cells, providing a comprehensive framework for understanding the interconnectedness of these pathways ( 8 , 33 - 40 , 49 ). The comprehension of mPRs’ role in tumorigenesis has undergone an evolving process, in contrast to the well-established classic nPRs.…”

Section: Inception Of Cmpn Signaling Networkmentioning

confidence: 99%

“…The CmPn signaling network has been proven to play a crucial role in breast cancer development. Long-term exposure to PRG has been associated with an increased risk of breast cancer ( 10 ), further emphasizing the significance of this network in tumorigenesis ( 8 , 33 - 40 ). The discovery of the role of CmPn signaling network and tumorigenesis has sparked further investigation into their potential role in early detection.…”

Section: Inception Of Cmpn Signaling Networkmentioning

confidence: 99%

“…The CSC can modulate the interaction between mPRs and nPRs, merging these pathways into CmPn signal networks ( Figure 2 ) ( 33 ). These signal networks are relevant in other types of tumorigenesis and vascular malformation during angiogenesis ( 8 , 33 - 40 ). The feedback regulation between PRG-mediated signaling and the CSC signaling within the CmPn signal network plays a crucial role in breast cancer development ( 41 ).…”

Section: Introductionmentioning

confidence: 99%

“…The feedback regulation between PRG-mediated signaling and the CSC signaling within the CmPn signal network plays a crucial role in breast cancer development ( 41 ). Long-term exposure to PRG is associated with increased breast cancer risk ( 10 ), highlighting the significance of this network in tumorigenesis ( 8 , 33 - 40 ). Considering the influence of factors on the CmPn signaling network, various elements like trace minerals, antagonists, and agonists for PRs (mPRs/nPRs) have been considered for their potential application in breast cancer prevention and treatment ( 8 , 33 - 36 , 42 - 44 ).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Biomarkers derived from CmP signal network in triple negative breast cancers

Sanchez,

Harvey,

Vincent

et al. 2023

Transl Breast Cancer Res

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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.

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Decreased renal expression of PAQR5 is associated with the absence of a nephroprotective effect of progesterone in a rat UUO model

Abramicheva

Семенович

Zorova

et al. 2023

Sci Rep

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Fibrosis is a severe complication of chronic kidney disease (CKD). Progesterone, like other sex hormones, plays an important role in renal physiology, but its role in CKD is poorly understood. We investigated progesterone effect on renal fibrosis progression in the rat model of unilateral ureteral obstruction (UUO). Female rats were exposed to UUO, ovariectomy and progesterone administration after UUO with ovariectomy. Expression of key fibrosis markers, proinflammatory cytokines, levels of membrane-bound (PAQR5) and nuclear (PGR) progesterone receptors, and matrix metalloproteinase (MMP) activity were analyzed in the obstructed and intact rat kidney. In all groups exposed to UUO, decreased PAQR5 expression was observed in the obstructed kidney while in the contralateral kidney, it remained unaffected. We found increased mRNA levels for profibrotic COL1A1, FN1, MMP2, TIMP1, TIMP2, proinflammatory IL1α, IL1β, and IL18, as well as elevated α-SMA and MMP9 proteins, collagen deposition, and MMP2 activity in all UUO kidneys. Progesterone had slight or no effect on the change in these markers. Thus, we demonstrate for the first time diminished sensitivity of the kidney to progesterone associated with renal fibrosis due to a severe decrease in PAQR5 expression that was accompanied by the lack of nephroprotection in a rat UUO model.

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Membrane Progesterone Receptors (mPRs/PAQRs) Are Going beyond Its Initial Definitions

Cited by 10 publications

References 162 publications

Familial CCM Genes Might Not Be Main Drivers for Pathogenesis of Sporadic CCMs-Genetic Similarity between Cancers and Vascular Malformations

Familial CCM Genes Might Not Be Main Drivers for Pathogenesis of Sporadic CCMs-Genetic Similarity between Cancers and Vascular Malformations

Biomarkers derived from CmP signal network in triple negative breast cancers

Decreased renal expression of PAQR5 is associated with the absence of a nephroprotective effect of progesterone in a rat UUO model

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