RESUMEN
Progesterone (PRG) is a key cyclical reproductive hormone that has a significant impact on female organs in vertebrates. It is mainly produced by the corpus luteum of the ovaries, but can also be generated from other sources such as the adrenal cortex, Leydig cells of the testes and neuronal and glial cells. PRG has wide-ranging physiological effects, including impacts on metabolic systems, central nervous systems and reproductive systems in both genders. It was first purified as an ovarian steroid with hormonal function for pregnancy, and is known to play a role in pro-gestational proliferation during pregnancy. The main function of PRG is exerted through its binding to progesterone receptors (nPRs, mPRs/PAQRs) to evoke cellular responses through genomic or non-genomic signaling cascades. Most of the existing research on PRG focuses on classic PRG-nPR-paired actions such as nuclear transcriptional factors, but new evidence suggests that PRG also exerts a wide range of PRG actions through non-classic membrane PRG receptors, which can be divided into two sub-classes: mPRs/PAQRs and PGRMCs. The review will concentrate on recently found non-classical membrane progesterone receptors (mainly mPRs/PAQRs) and speculate their connections, utilizing the present comprehension of progesterone receptors.
RESUMEN
It is well-known that serum and cellular concentrations of zinc are altered in breast cancer patients. Specifically, there are notable zinc hyper-aggregates in breast tumor cells when compared to normal mammary epithelial cells. However, the mechanisms responsible for zinc accumulation and the consequences of zinc dysregulation are poorly understood. In this review, we detailed cellular zinc regulation/dysregulation under the influence of varying levels of sex steroids and breast cancer tumorigenesis to try to better understand the intricate relationship between these factors based on our current understanding of the CmPn/CmP signaling network. We also made some efforts to propose a relationship between zinc signaling and the CmPn/CmP signaling network.
Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Transformación Celular Neoplásica , Carcinogénesis , Transducción de Señal , ZincRESUMEN
Cerebral cavernous malformations (CCMs) are characterized by abnormally dilated intracranial microvascular sinusoids that result in increased susceptibility to hemorrhagic stroke. It has been demonstrated that three CCM proteins (CCM1, CCM2, and CCM3) form the CCM signaling complex (CSC) to mediate angiogenic signaling. Disruption of the CSC will result in hemorrhagic CCMs, a consequence of compromised blood-brain barrier (BBB) integrity. Due to their characteristically incomplete penetrance, the majority of CCM mutation carriers (presumed CCM patients) are largely asymptomatic, but when symptoms occur, the disease has typically reached a clinical stage of focal hemorrhage with irreversible brain damage. We recently reported that the CSC couples both classic (nuclear; nPRs) and nonclassic (membrane; mPRs) progesterone (PRG)-receptors-mediated signaling within the CSC-mPRs-PRG (CmP) signaling network in nPR(-) breast cancer cells. In this report, we demonstrate that depletion of any of the three CCM genes or treatment with mPR-specific PRG actions (PRG/mifepristone) results in the disruption of the CmP signaling network, leading to increased permeability in the nPR(-) endothelial cells (ECs) monolayer in vitro. Finally, utilizing our in vivo hemizygous Ccm mutant mice models, we demonstrate that depletion of any of the three CCM genes, in combination with mPR-specific PRG actions, is also capable of leading to defective homeostasis of PRG in vivo and subsequent BBB disruption, allowing us to identify a specific panel of etiological blood biomarkers associated with BBB disruption. To our knowledge, this is the first report detailing the etiology to predict the occurrence of a disrupted BBB, an indication of early hemorrhagic events.
Asunto(s)
Células Endoteliales , Hemangioma Cavernoso del Sistema Nervioso Central , Animales , Barrera Hematoencefálica/metabolismo , Citidina Monofosfato/metabolismo , Células Endoteliales/metabolismo , Hemangioma Cavernoso del Sistema Nervioso Central/genética , Ratones , Proteínas Asociadas a Microtúbulos/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Breast cancer, the most diagnosed cancer, remains the second leading cause of cancer death in the United States, and excessive Progesterone (PRG) or Mifepristone (MIF) exposure may be at an increased risk for developing breast cancer. PRG exerts its cellular responses through signaling cascades involving classic, non-classic, or combined responses by binding to either classic nuclear PRG receptors (nPRs) or non-classic membrane PRG receptors (mPRs). Currently, the intricate balance and switch mechanisms between these two signaling cascades remain elusive. Three genes, CCM1-3, form the CCM signaling complex (CSC) which mediates multiple signaling cascades. METHODS: Utilizing molecular, cellular, Omics, and systems biology approaches, we analyzed the relationship among the CSC, PRG, and nPRs/mPRs during breast cancer tumorigenesis. RESULTS: We discovered that the CSC plays an essential role in coupling both classic and non-classic PRG signaling pathways by mediating crosstalk between them, forming the CmPn (CSC-mPRs-PRG-nPRs) signaling network. We found that mPR-specific PRG actions (PRG + MIF) play an essential role in this CmPn network during breast cancer tumorigenesis. Additionally, we have identified 4 categories of candidate biomarkers (9 intrinsic, 2 PRG-inducible, 1 PRG-repressive, 1 mPR-specific PRG-repressive, and 2 mPR-responsive) for Luminal-A breast cancers during tumorigenesis and have confirmed the prognostic application of RPL13 and RPL38 as intrinsic biomarkers using a dual validation method. CONCLUSIONS: We have discovered that the CSC plays an essential role in the CmPn signaling network for Luminal-A breast cancers with identification of two intrinsic biomarkers. Video Abstract.