<p>Dual targeting of estrogen receptor α and estrogen-related receptor α: a novel endocrine therapy for endometrial cancer</p>

Abstract

BackgroundEndometrial cancer (EC) is a hormone dependent carcinoma that may involve complex molecular mechanisms. Endocrine therapy by blocking the estrogen and estrogen receptor α (ERα) has been effective in breast cancer, while it is still controversial in EC. Recently, estrogen-related receptor α (ERRα) was proven to be another endocrine therapy target.MethodsThe anti-tumor effect of selective estrogen receptor modulators (SERMs) and XCT790 (XCT) used alone or in combination were evaluated in both of ERα-positive (ERα+) and ERα-negative (ERα-) EC cells. ERα and ERRα mRNA were tested by qPCR, while the protein was detected by Western blot. The proliferation was tested by MTS and cell cycle, apoptosis rate were analyzed by flow cytometry.ResultsA relatively high dose (10 μM) of tamoxifen (TAM) suppressed the expression of ERα and ERRα in two types of EC cells. However, 10 μM raloxifene (RAL) exhibited no effect on ERα and ERRα, while 10 μM XCT down regulated ERRα specifically, but not ERα in all EC cells. When dual targeting on ERα and ERRα by combining TAM with XCT, the proliferation inhibitory effect and apoptosis reached the strongest in all EC cells (P<0.05). Moreover, the inhibitory effect of proliferation was attributed significantly to the G0/G1 arrest (P<0.05). Interestingly, the apoptosis induced by combining TAM with XCT were obviously higher in ERα+ EC cells than ERα- EC cells (P<0.05).ConclusionTaken together, the results indicate that dual targeting on ERα and ERRα represents a better anti-tumor effect, which provides a novel endocrine based therapy strategy for EC.

Androgens, oestrogens and endometrium: a fine balance between perfection and pathology

“…The SERD fulvestrant/faslodex (Table 2) has been investigated as a treatment for endometrial cancer in phase I/II trials, although well-tolerated, it has low oral bioavailability and further trials are needed (Bogliolo et al 2017). Another recent study suggested dual targeting of ERα with tamoxifen and ERRα with XCT790 may be beneficial for EC treatment, but this requires further validation (Mao et al 2019). While administration of SERMs/SERDs may be appropriate for postmenopausal women with cancer, their use in younger women with non-malignant endometrial disorders such as endometriosis is more challenging with data limited to promising results in preclinical models (Kulak et al 2011, Khine et al 2018.…”

Lipid Reprogramming Induced by TFEB-ERRα Axis Enhanced Membrane Fluidity to Promote EC Progression

“…Guo found dramatic increases in lipid biosynthesis and lipid peroxidation in a genetically engineered mouse model of endometrioid adenocarcinoma 22 , suggesting that lipidomic changes or reprogramming are signi cant in EC. Previous studies have con rmed that downregulation of ERRα provides a potential therapeutic strategy and inhibits cellular metastasis and invasion in EC 11,25 . However, the mechanism by which ERRα regulates FA and GP synthesis was unexplored prior to our study.…”

“…Moreover, ERRα-mediated signaling pathways have recently emerged as key factors in the regulation of cancer lipid metabolism. In our previous work, the translational factor activity of TFEB was affected by the downregulation of ERRα expression in EC according to a high-throughput DNA/protein assay 25 , which suggested that TFEB should interact with ERRα and be involved in EC lipid reprogramming and progression, which triggered our interest. TFEB downregulation or de ciency can obviously affect the cellular phenotype in a physiologically relevant manner in settings including atherosclerosis 26 , nonalcoholic fatty liver disease 27 , cancer 28 and neurodegeneration 29 .…”

“…Guo et al suggested that metformin signi cantly reversed obesity-driven lipid and protein biosynthesis upregulation in an obese LKB1 / p53 / mouse model of EC 22 . Recently, an increasing number of studies have con rmed that ERRα is a key regulator of metabolism in obesity-related tumors, such as breast cancer 23 , prostate cancer 24 , and EC 25 . Moreover, ERRα-mediated signaling pathways have recently emerged as key factors in the regulation of cancer lipid metabolism.…”

Lipid reprogramming induced by the TFEB-ERRα axis enhanced membrane fluidity to promote EC progression

“…Guo et al suggested that metformin significantly reversed obesity-driven lipid and protein biosynthesis upregulation in an obese LKB1 fl/fl p53 fl/fl mouse model of EC [ 22 ]. Recently, an increasing number of studies have confirmed that ERRα is a key regulator of metabolism in obesity-related tumors, such as breast cancer [ 23 ], prostate cancer [ 24 ], and EC [ 25 ]. Moreover, ERRα-mediated signaling pathways have recently emerged as key factors in the regulation of cancer lipid metabolism.…”