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Estrogen receptor α (ERα) is the dominant tumorigenesis driver in breast cancer (BC), and ERα-positive BC (ERα+ BC) accounts for more than two-thirds of BC cases. MOF (males absent on the first) is a highly conserved histone acetyltransferase that acetylates lysine 16 of histone H4 (H4K16) and several non-histone proteins. Unbalanced expression of MOF has been identified, and high MOF expression predicted a favorable prognosis in BC. However, the association of MOF with ERα and the regulatory mechanisms of MOF in ERα signaling remain elusive. Our study revealed that the expression of MOF is negatively correlated with that of ERα in BC. In ERα+ BC cells, MOF overexpression downregulated the protein abundance of ERα in both cytoplasm and nucleus, thus attenuating ERα-mediated transactivation as well as cellular proliferation and in vivo tumorigenicity of BC cells. MOF promoted ERα protein degradation through CUL4B-mediated ubiquitin-proteasome pathway and induced HSP90 hyperacetylation that led to the loss of chaperone protection of HSP90 to ERα. We also revealed that suppression of MOF restored ERα expression and increased the sensitivity of ERα-negative BC cells to tamoxifen treatment. These results provide a new insight into the tumor-suppressive role of MOF in BC via negatively regulating ERα action, suggesting that MOF might be a potential therapeutic target for BC. [ABSTRACT FROM AUTHOR]

The incidence of thyroid cancer was predominant in women, indicating that the sex hormone may have a role in thyroid cancer development. Generally, the sex hormone exerts its function by binding to the correspondent nuclear receptors. Therefore, aberrant of these receptors may be involved in the development of thyroid cancer. Estrogen receptor alpha (ERα) and beta (ERβ), two main estrogen receptors, have been reported to have an important role in the pathogenesis of thyroid cancer. When the ERα and ERβ genes undergo the alternative RNA splicing, some ERα and ERβ isoforms with incomplete functional domains may be formed. To date, several isoforms of ERα and ERβ have been identified. However, their expression and roles in thyroid cancer are far from clear. In this review, we summarized the expressions and roles of ERα and ERβ isoforms in thyroid cancer, aiming to provide the perspective of modulating the alternative RNA splicing of ERα and ERβ against thyroid cancer. [ABSTRACT FROM AUTHOR]

The incidence of thyroid cancer was predominant in women, indicating that the sex hormone may have a role in thyroid cancer development. Generally, the sex hormone exerts its function by binding to the correspondent nuclear receptors. Therefore, aberrant of these receptors may be involved in the development of thyroid cancer. Estrogen receptor alpha (ERα) and beta (ERβ), two main estrogen receptors, have been reported to have an important role in the pathogenesis of thyroid cancer. When the ERα and ERβ genes undergo the alternative RNA splicing, some ERα and ERβ isoforms with incomplete functional domains may be formed. To date, several isoforms of ERα and ERβ have been identified. However, their expression and roles in thyroid cancer are far from clear. In this review, we summarized the expressions and roles of ERα and ERβ isoforms in thyroid cancer, aiming to provide the perspective of modulating the alternative RNA splicing of ERα and ERβ against thyroid cancer.

Background: Among women, breast cancer is the leading cause of cancer-related death worldwide. Estrogen receptor α-positive (ERα+) breast cancer accounts for 70% of all breast cancer subtypes. Although ERα+ breast cancer initially responds to estrogen deprivation or blockade, the emergence of resistance compels the use of more aggressive therapies. While ERα is a driver in ERα+ breast cancer, ERβ plays an inhibitory role in several different cancer types. To date, the lack of highly selective ERβ agonists without ERα activity has limited the exploration of ERβ activation as a strategy for ERα+ breast cancer. Methods: We measured the expression levels of ESR1 and ESR2 genes in immortalized mammary epithelial cells and different breast cancer cell lines. The viability of ERα+ breast cancer cell lines upon treatments with specific ERβ agonists, including OSU-ERb-12 and LY500307, was assessed. The specificity of the ERβ agonists, OSU-ERb-12 and LY500307, was confirmed by reporter assays. The effects of ERβ agonists on cell proliferation, cell cycle, apoptosis, colony formation, cell migration, and expression of tumor suppressor proteins were analyzed. The expression of ESR2 and genes containing ERE-AP1 composite response elements was examined in ERα+ human breast cancer samples to determine the correlation between ESR2 expression and overall survival and that of putative ESR2 -regulated genes. Results: In this study, we demonstrate the efficacy of highly selective ERβ agonists in ERα+ breast cancer cell lines and drug-resistant derivatives. ERβ agonists blocked cell proliferation, migration, and colony formation and induced apoptosis and S and/or G2/M cell-cycle arrest of ERα+ breast cancer cell lines. Also, increases in the expression of the key tumor suppressors FOXO1 and FOXO3a were noted. Importantly, the strong synergy between ERβ agonists and ERα antagonists suggested that the efficacy of ERβ agonists is maximized by combination with ERα blockade. Lastly, ESR2 (ERβ gene) expression was negatively correlated with ESR1 (ERα gene) and CCND1 RNA expression in human metastatic ERα+/HER2- breast cancer samples. Conclusion: Our results demonstrate that highly selective ERβ agonists attenuate the viability of ERα+ breast cancer cell lines in vitro and suggest that this therapeutic strategy merits further evaluation for ERα+ breast cancer. [ABSTRACT FROM AUTHOR]

BackgroundAmong women, breast cancer is the leading cause of cancer-related death worldwide. Estrogen receptor α-positive (ERα+) breast cancer accounts for 70% of all breast cancer subtypes. Although ERα+ breast cancer initially responds to estrogen deprivation or blockade, the emergence of resistance compels the use of more aggressive therapies. While ERα is a driver in ERα+ breast cancer, ERβ plays an inhibitory role in several different cancer types. To date, the lack of highly selective ERβ agonists without ERα activity has limited the exploration of ERβ activation as a strategy for ERα+ breast cancer.MethodsWe measured the expression levels of ESR1 and ESR2 genes in immortalized mammary epithelial cells and different breast cancer cell lines. The viability of ERα+ breast cancer cell lines upon treatments with specific ERβ agonists, including OSU-ERb-12 and LY500307, was assessed. The specificity of the ERβ agonists, OSU-ERb-12 and LY500307, was confirmed by reporter assays. The effects of ERβ agonists on cell proliferation, cell cycle, apoptosis, colony formation, cell migration, and expression of tumor suppressor proteins were analyzed. The expression of ESR2 and genes containing ERE-AP1 composite response elements was examined in ERα+ human breast cancer samples to determine the correlation between ESR2 expression and overall survival and that of putative ESR2-regulated genes.ResultsIn this study, we demonstrate the efficacy of highly selective ERβ agonists in ERα+ breast cancer cell lines and drug-resistant derivatives. ERβ agonists blocked cell proliferation, migration, and colony formation and induced apoptosis and S and/or G2/M cell-cycle arrest of ERα+ breast cancer cell lines. Also, increases in the expression of the key tumor suppressors FOXO1 and FOXO3a were noted. Importantly, the strong synergy between ERβ agonists and ERα antagonists suggested that the efficacy of ERβ agonists is maximized by combination with ERα blockade. Lastly, ESR2 (ERβ gene) expression was negatively correlated with ESR1 (ERα gene) and CCND1 RNA expression in human metastatic ERα+/HER2- breast cancer samples.ConclusionOur results demonstrate that highly selective ERβ agonists attenuate the viability of ERα+ breast cancer cell lines in vitro and suggest that this therapeutic strategy merits further evaluation for ERα+ breast cancer.

Objective: The curative effect of high-efficiency progesterone and other therapeutic drugs for endometrioid adenocarcinoma patients with preservation of reproductive capacity has not been satisfactory so far. Novel therapeutic drugs need to be explored. Methods: We investigated the cytoplastic and nuclear expression levels of LMTK3 between endometrioid adenocarcinoma tissues and adjacent endometrial tissues by immunohistochemistry. We detected the effects of LMTK3 on cell viability of Ishikawa cells by CCK-8. We detected the effects of LMTK3 on cell cycle and apoptosis of Ishikawa cells by flow cytometry. We also detected the effects of LMTK3 knockdown on mRNA and protein levels of ERα by qRT-PCR and western blotting, respectively. We also used the cBioPortal online database to analyze the coexpression of LMTK3 and ESR1 in 1647 UCEC samples. Results: We used TMAs to identify that LMTK3 was mainly detected in the cytoplasm of endometrioid tissues, and cytoplasmic LMTK3 expression in endometrioid tissues was higher than that in adjacent endometrial tissues (P < 0.05). LMTK3 knockdown decreased the proliferation of Ishikawa cells through decreasing cell viability (P < 0.01), increasing G1 (P < 0.001) arrest, and promoting apoptosis (P < 0.01). There was a positive correlation between the mRNA expression levels of LMTK3 and ESR1 (Spearman: P =2.011e-5, R=0.13; Pearson: P =7.18e-8, R=0.17). Knockdown of LMTK3 also reduced the mRNA (P < 0.001) and protein (P < 0.001) levels of ERα. Conclusions: Inhibitors of LMTK3 may be a possible future treatment for ERα and LMTK3 highly expressed endometrioid adenocarcinoma following appropriate studies. [ABSTRACT FROM AUTHOR]

ObjectiveThe curative effect of high-efficiency progesterone and other therapeutic drugs for endometrioid adenocarcinoma patients with preservation of reproductive capacity has not been satisfactory so far. Novel therapeutic drugs need to be explored.MethodsWe investigated the cytoplastic and nuclear expression levels of LMTK3 between endometrioid adenocarcinoma tissues and adjacent endometrial tissues by immunohistochemistry. We detected the effects of LMTK3 on cell viability of Ishikawa cells by CCK-8. We detected the effects of LMTK3 on cell cycle and apoptosis of Ishikawa cells by flow cytometry. We also detected the effects of LMTK3 knockdown on mRNA and protein levels of ERα by qRT-PCR and western blotting, respectively. We also used the cBioPortal online database to analyze the coexpression of LMTK3 and ESR1 in 1647 UCEC samples.ResultsWe used TMAs to identify that LMTK3 was mainly detected in the cytoplasm of endometrioid tissues, and cytoplasmic LMTK3 expression in endometrioid tissues was higher than that in adjacent endometrial tissues (P < 0.05). LMTK3 knockdown decreased the proliferation of Ishikawa cells through decreasing cell viability (P < 0.01), increasing G1 (P < 0.001) arrest, and promoting apoptosis (P < 0.01). There was a positive correlation between the mRNA expression levels of LMTK3 and ESR1 (Spearman: P=2.011e-5, R=0.13; Pearson: P=7.18e-8, R=0.17). Knockdown of LMTK3 also reduced the mRNA (P < 0.001) and protein (P < 0.001) levels of ERα.ConclusionsInhibitors of LMTK3 may be a possible future treatment for ERα and LMTK3 highly expressed endometrioid adenocarcinoma following appropriate studies.

Estrogen receptor α (ERα) is the major driver for breast tumor carcinogenesis and progression, while ERα positive breast cancer is the major subtype in breast malignancies, which account for 70% breast cancers in patients. The success of endocrine therapy such as tamoxifen is one of the biggest breakthroughs in breast cancer treatments. However, the endocrine therapy resistance is a headache problem in breast cancer. Further mechanisms need to be identified to the effect of ERα signaling in controlling breast cancer progression and drug resistance. HOIL-1 was firstly identified as the ERα transcriptional co-activator in modulating estrogen signaling in breast cancer. In our current study, we showed that HOIL-1, which was elevated in breast cancer, related to good prognosis in ERα positive breast cancer, but correlated with poor outcome in endocrine-treated patients. HOIL-1 was required for ERα positive breast cancer proliferation and clone formation, which effect could be rescued by further ERα overexpression. Further mechanism studies showed that HOIL-1 is required for ERα signaling activity in breast cancer cells. HOIL-1 could interact with ERα in the cytosol and modulate ERα stability via inhibiting ERα K48-linked poly-ubiquitination. Thus, our study demonstrated a novel post-translational modification in ERα signaling, which could provide novel strategy for ERα-driven breast cancer therapy.

Estrogen receptor α (ERα) is the major driver for breast tumor carcinogenesis and progression, while ERα positive breast cancer is the major subtype in breast malignancies, which account for 70% breast cancers in patients. The success of endocrine therapy such as tamoxifen is one of the biggest breakthroughs in breast cancer treatments. However, the endocrine therapy resistance is a headache problem in breast cancer. Further mechanisms need to be identified to the effect of ERα signaling in controlling breast cancer progression and drug resistance. HOIL-1 was firstly identified as the ERα transcriptional co-activator in modulating estrogen signaling in breast cancer. In our current study, we showed that HOIL-1, which was elevated in breast cancer, related to good prognosis in ERα positive breast cancer, but correlated with poor outcome in endocrine-treated patients. HOIL-1 was required for ERα positive breast cancer proliferation and clone formation, which effect could be rescued by further ERα overexpression. Further mechanism studies showed that HOIL-1 is required for ERα signaling activity in breast cancer cells. HOIL-1 could interact with ERα in the cytosol and modulate ERα stability via inhibiting ERα K48-linked poly-ubiquitination. Thus, our study demonstrated a novel post-translational modification in ERα signaling, which could provide novel strategy for ERα-driven breast cancer therapy. [ABSTRACT FROM AUTHOR]

The molecular mechanisms by which uterine leiomyoma (UL) cells proliferate are unclear. Long noncoding RNA (lncRNA) is reported to participate in the occurrence and development of gynecological cancers. We investigated the molecular mechanisms that lncRNA uses in UL. We found that lncRNA Alu-mediated p21 transcriptional regulator (APTR) showed higher expression in UL tumor tissues compared with that in normal uterine tissues. APTR induced cell proliferation and colony formation both in vitro and in vivo. The JASPAR database showed that APTR was likely interacted with ERα, and these molecules were identified via laser scanning confocal microscopy and RNA immunoprecipitation analysis. To verify the correlation between APTR and ERα, we overexpressed and underexpressed APTR and simultaneously expressed ERα. The results showed that APTR function was suppressed. APTR increased the expressions of the proteins in the Wnt pathway, and inhibiting ERα eliminated these responses. In conclusion, our data suggest that APTR promoted leiomyoma cell proliferation through the Wnt pathway by targeting ERα, suggesting a new role of APTR in the Wnt signaling pathway in UL.

The molecular mechanisms by which uterine leiomyoma (UL) cells proliferate are unclear. Long noncoding RNA (lncRNA) is reported to participate in the occurrence and development of gynecological cancers. We investigated the molecular mechanisms that lncRNA uses in UL. We found that lncRNA Alu-mediated p21 transcriptional regulator (APTR) showed higher expression in UL tumor tissues compared with that in normal uterine tissues. APTR induced cell proliferation and colony formation both in vitro and in vivo. The JASPAR database showed that APTR was likely interacted with ERα, and these molecules were identified via laser scanning confocal microscopy and RNA immunoprecipitation analysis. To verify the correlation between APTR and ERα, we overexpressed and underexpressed APTR and simultaneously expressed ERα. The results showed that APTR function was suppressed. APTR increased the expressions of the proteins in the Wnt pathway, and inhibiting ERα eliminated these responses. In conclusion, our data suggest that APTR promoted leiomyoma cell proliferation through the Wnt pathway by targeting ERα, suggesting a new role of APTR in the Wnt signaling pathway in UL. [ABSTRACT FROM AUTHOR]

Estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) belong to a superfamily of nuclear receptors called steroid hormone receptors, which, upon binding ligand, dimerize and translocate to the nucleus where they activate or repress the transcription of a large number of genes, thus modulating critical physiologic processes. ERβ has multiple isoforms that show differing association with prognosis. Expression levels of the full length ERβ1 isoform are often lower in aggressive cancers as compared to normal tissue. High ERβ1 expression is associated with improved overall survival in women with breast cancer. The promise of ERβ activation, as a potential targeted therapy, is based on concurrent activation of multiple tumor suppressor pathways with few side effects compared to chemotherapy. Thus, ERβ is a nuclear receptor with broad-spectrum tumor suppressor activity, which could serve as a potential treatment target in a variety of human cancers including breast cancer. Further development of highly selective agonists that lack ERα agonist activity, will be necessary to fully harness the potential of ERβ.

Estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) belong to a superfamily of nuclear receptors called steroid hormone receptors, which, upon binding ligand, dimerize and translocate to the nucleus where they activate or repress the transcription of a large number of genes, thus modulating critical physiologic processes. ERβ has multiple isoforms that show differing association with prognosis. Expression levels of the full length ERβ1 isoform are often lower in aggressive cancers as compared to normal tissue. High ERβ1 expression is associated with improved overall survival in women with breast cancer. The promise of ERβ activation, as a potential targeted therapy, is based on concurrent activation of multiple tumor suppressor pathways with few side effects compared to chemotherapy. Thus, ERβ is a nuclear receptor with broad-spectrum tumor suppressor activity, which could serve as a potential treatment target in a variety of human cancers including breast cancer. Further development of highly selective agonists that lack ERα agonist activity, will be necessary to fully harness the potential of ERβ. [ABSTRACT FROM AUTHOR]

Estrogen receptor α (ERα) is the dominant tumorigenesis driver in breast cancer (BC), and ERα-positive BC (ERα+ BC) accounts for more than two-thirds of BC cases. MOF (males absent on the first) is a highly conserved histone acetyltransferase that acetylates lysine 16 of histone H4 (H4K16) and several non-histone proteins. Unbalanced expression of MOF has been identified, and high MOF expression predicted a favorable prognosis in BC. However, the association of MOF with ERα and the regulatory mechanisms of MOF in ERα signaling remain elusive. Our study revealed that the expression of MOF is negatively correlated with that of ERα in BC. In ERα+ BC cells, MOF overexpression downregulated the protein abundance of ERα in both cytoplasm and nucleus, thus attenuating ERα-mediated transactivation as well as cellular proliferation and in vivo tumorigenicity of BC cells. MOF promoted ERα protein degradation through CUL4B-mediated ubiquitin-proteasome pathway and induced HSP90 hyperacetylation that led to the loss of chaperone protection of HSP90 to ERα. We also revealed that suppression of MOF restored ERα expression and increased the sensitivity of ERα-negative BC cells to tamoxifen treatment. These results provide a new insight into the tumor-suppressive role of MOF in BC via negatively regulating ERα action, suggesting that MOF might be a potential therapeutic target for BC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Yang, Li, Wu, Liu, Zhao, Zhu, Xie and Li.)