1,721,051 research outputs found
PMM2 controls ERα levels and cell proliferation in ESR1 Y537S variant expressing breast cancer cells
Full text linkPurpose: Metabolic reprogramming in breast cancer (BC) subtypes offers potential personalized treatment targets. Estrogen receptor α (ERα)-positive BC patients undergoing endocrine therapy (ET) can develop ET-resistant metastatic disease. Specific mutations, like Y537S in ERα, drive uncontrolled cell proliferation. Targeting mutant receptor levels shows promise for inhibiting growth in metastatic BC expressing ERα variants. Additionally, metabolic reprogramming occurs in ERα Y537S mutant cells. Consequently, we conducted a screen to identify metabolic proteins reducing intracellular levels of ERα Y537S and inhibiting cell proliferation. Methods: Nine metabolic proteins were identified in a siRNA-based screen, with phosphomannose mutase 2 (PMM2) showing the most promise. We measured the impact of PMM2 depletion on ERα stability and cell proliferation in ERα Y537S mutant cells. Additionally, we tested the effect of PMM2 reduction on the hyperactive phenotype of the mutant and its proliferation when combined with metastatic BC treatment drugs. Results: PMM2 emerged as a significant target due to its correlation with better relapse-free survival, overexpression in ERα-positive tumors, and its elevation in ERα Y537S-expressing cells. Depletion of PMM2 induces degradation of ERα Y537S, inhibits cell proliferation, and reduces ERα signaling. Notably, reducing PMM2 levels re-sensitizes ERα Y537S-expressing cells to certain ET drugs and CDK4/CDK6 inhibitors. Mechanistically, depletion of PMM2 leads to a reduction in ESR1 mRNA levels, resulting in decreased ERα receptor protein expression. Furthermore, reduction of PMM2 decreases FOXA1 levels, which plays a crucial role in ERα regulation. Conclusions: Our findings establish PMM2 as an innovative therapeutic target for metastatic BC expressing the ERα Y537S variant, offering alternative strategies for managing and treating this disease
Signaling regulation of genomic and nongenomic functions of estrogen receptors
No full textEstrogen receptors (ERs) mediate the effects of 17b-estradiol under physiologic and pathologic conditions. ERs trigger 17bestradiol-
sensitive gene transcription by binding to specific estrogen response elements (i.e. genomic mechanism). The cellular
effects of estrogen are also influenced by membrane- or cytoplasm-initiated responses (i.e. nongenomic mechanism). Both ERevoked
genomic and nongenomic effects originate from a unique signaling network. Furthermore, estrogen-initiated rapid
pathways and ERa interactions with specific partners (e.g. AIB1, PELP1/MNAR; MTA1, MTA1s and p130Cas) influence both
ER functions. Here, we summarize the recent findings related to multiple regulatory levels of the signaling networks responsible
for ERs-mediated responses in breast cancer cells
Xenoestrogen regulation of ERα/ERβ balance in hormone-associated cancers.
No full textThe hormone 17β-estradiol (E2) contributes to body homeostasis maintenance by regulating many different physiological functions in both male and female organs. E2 actions in reproductive and non-reproductive tissues rely on a complex net of nuclear and extra-nuclear signal transduction pathways triggered by at least two estrogen receptor subtypes (ERα and ERβ). Consequently, the de-regulation of E2:ER signaling contributes to the pathogenesis of many diseases including cancer. Among other factors, the ERα/ERβ ratio is considered one of the pivotal mechanisms at the root of E2 action in cancer progression. Remarkably, several natural or synthetic exogenous chemicals, collectively called xenoestrogens, bind to ERs and interfere with their signals and intracellular functions. In this review, the molecular mechanism(s) through which xenoestrogens influence ERα and ERβ intracellular concentrations and the consequences of this influence on E2-related cancer will be discussed
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