Crosstalk between progesterone receptor membrane component 1 and estrogen receptor α promotes breast cancer cell proliferation

Pedroza, Diego A.; Subramani, Ramadevi; Tiula, Kira; Do, Anthony; Rashiraj, Navya; Galvez, Adriana; Chatterjee, Animesh; Bencomo, Alejandra; Rivera, Servando; Lakshmanaswamy, Rajkumar

doi:10.1038/s41374-021-00594-6

Cited by 27 publications

(18 citation statements)

References 59 publications

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“…At molecular level, although conflicting data are reported in literature regarding PGRMC1-initiated effects in breast cancer cells [ 165 ], PGRMC1 activation enhances PI3K/Akt/mTOR and EGFR-mediated signaling pathways, resulting in the increased proliferation [ 166 ] and alteration of lipid metabolism [ 167 ] in ER+ and triple-negative breast tumors. This is in line with the reported association between PGRMC1 and ER levels [ 160 ], the observed PGRMC1-mediated ERα activation [ 167 ] and the increased breast cancer cell proliferation correlated with PGRMC1-ERα crosstalk recently reported [ 168 ]. However, PGRMC1’s role in tumor development and progression is not limited to breast cancer.…”

Section: Membrane Steroid Receptors and Their Role In Hormone-sensitive Cancerssupporting

confidence: 92%

Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers

Masi

Racchi

Travelli

et al. 2021

Cells

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Cancer is one of the most common causes of death worldwide, and its development is a result of the complex interaction of genetic factors, environmental cues, and aging. Hormone-sensitive cancers depend on the action of one or more hormones for their development and progression. Sex steroids and corticosteroids can regulate different physiological functions, including metabolism, growth, and proliferation, through their interaction with specific nuclear receptors, that can transcriptionally regulate target genes via their genomic actions. Therefore, interference with hormones’ activities, e.g., deregulation of their production and downstream pathways or the exposition to exogenous hormone-active substances such as endocrine-disrupting chemicals (EDCs), can affect the regulation of their correlated pathways and trigger the neoplastic transformation. Although nuclear receptors account for most hormone-related biologic effects and their slow genomic responses are well-studied, less-known membrane receptors are emerging for their ability to mediate steroid hormones effects through the activation of rapid non-genomic responses also involved in the development of hormone-sensitive cancers. This review aims to collect pre-clinical and clinical data on these extranuclear receptors not only to draw attention to their emerging role in cancer development and progression but also to highlight their dual role as tumor microenvironment players and potential candidate drug targets.

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Section: Membrane Steroid Receptors and Their Role In Hormone-sensitive Cancerssupporting

confidence: 92%

Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers

Masi

Racchi

Travelli

et al. 2021

Cells

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“…The addition of AG-205 blocked the inhibitory effect of estradiol on zebrafish oocyte maturation, but the contribution of PGRMC1 to this mechanism and whether AG-205 did not modify estradiol concentration by modulating expression of metabolic enzymes remain to be confirmed. This would be extremely instructive since a link between PGRMC1, estradiol/estradiol receptor and breast cancer progression was evidenced in other reports that relied on downregulation [34] or overexpression [29] of PGRMC1, and are therefore not challenged by our study.…”

Section: Discussionmentioning

confidence: 59%

AG-205 Upregulates Enzymes Involved in Cholesterol Biosynthesis and Steroidogenesis in Human Endometrial Cells Independently of PGRMC1 and Related MAPR Proteins

et al. 2021

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An inappropriate response to progestogens in the human endometrium can result in fertility issues and jeopardize progestin-based treatments against pathologies such as endometriosis. PGRMC1 can mediate progesterone response in the breast and ovaries but its endometrial functions remain unknown. AG-205 is an alleged PGRMC1 inhibitor but its specificity was recently questioned. We added AG-205 in the cultures of two endometrial cell lines and performed a transcriptomic comparison. AG-205 significantly increased expression of genes coding enzymes of the cholesterol biosynthetic pathway or of steroidogenesis. However, these observations were not reproduced with cells transfected with siRNA against PGRMC1 or its related proteins (MAPRs). Furthermore, AG-205 retained its ability to increase expression of selected target genes even when expression of PGRMC1 or all MAPRs was concomitantly downregulated, indicating that neither PGRMC1 nor any MAPR is required to mediate AG-205 effect. In conclusion, although AG-205 has attractive effects encouraging its use to develop therapeutic strategies, for instance against breast cancer, our study delivers two important warning messages. First, AG-205 is not specific for PGRMC1 or other MAPRs and its mechanisms of action remain unclear. Second, due to its effects on genes involved in steroidogenesis, its use may increase the risk for endometrial pathologies resulting from imbalanced hormones concentrations.

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“…Pathways associated with cell cycle and cancers can be considered as surrogates for dedifferentiation. This is a testable hypothesis, which predicts that the AG-205 and PGRMC1 siRNA treatments will exhibit induced epigenetic changes in the MDA-MB-468 cell system of Pedroza et al [454].…”

Section: Cpg Epigenetic Regulationmentioning

confidence: 95%

Unde venisti PGRMC? Grand-Scale Biology from Early Eukaryotes and Eumetazoan Animal Origins

Cahill¹

2022

Front. Biosci. (Landmark Ed)

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The title usage of Unde venisti 'from where have you come' is from a now dead language (Latin) that foundationally influenced modern English (not the major influence, but an essential formative one). This is an apt analogy for how both the ancient eukaryotic and eumetazoan functions of PGRMC proteins (PGRMC1 and PGRMC2 in mammals) probably influence modern human biology: via a formative trajectory from an evolutionarily foundational fulcrum. There is an arguable probability, although not a certainty, that PGRMC-like proteins were involved in eukaryogenesis. If so, then the proto-eukaryotic ancestral protein is modelled as having initiated the oxygeninduced and CYP450 (Cytochrome P450)-mediated synthesis of sterols in the endoplasmic reticulum to regulate proto-mitochondrial activity and heme homeostasis, as well as having enabled sterol transport between endoplasmic reticulum (ER) and mitochondria membranes involving the actin cytoskeleton, transport of heme from mitochondria, and possibly the regulation/origins of mitosis/meiosis. Later, during animal evolution, the last eumetazoan common ancestor (LEUMCA) acquired PGRMC phosphorylated tyrosines coincidentally with the gastrulation organizer, Netrin/deleted in colorectal carcinoma (DCC) signaling, muscle fibers, synapsed neurons, and neural recovery via a sleep-like process. Modern PGRMC proteins regulate multiple functions, including CYP450-mediated steroidogenesis, membrane trafficking, heme homeostasis, glycolysis/Warburg effect, fatty acid metabolism, mitochondrial regulation, and genomic CpG epigenetic regulation of gene expression. The latter imposes the system of differentiation status-sensitive cell-type specific proteomic complements in multi-tissued descendants of the LEUMCA. This paper attempts to trace PGRMC functions through time, proposing that key functions were involved in early eukaryotes, and were later added upon in the LEUMCA. An accompanying paper considers the implications of this awareness for human health and disease.

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Crosstalk between progesterone receptor membrane component 1 and estrogen receptor α promotes breast cancer cell proliferation

Cited by 27 publications

References 59 publications

Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers

Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers

AG-205 Upregulates Enzymes Involved in Cholesterol Biosynthesis and Steroidogenesis in Human Endometrial Cells Independently of PGRMC1 and Related MAPR Proteins

Unde venisti PGRMC? Grand-Scale Biology from Early Eukaryotes and Eumetazoan Animal Origins

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