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Histone methyltransferases regulate the transcriptional expression of ER? and the proliferation of tamoxifen-resistant breast cancer cells.

ABSTRACT: PURPOSE:Although tamoxifen remains the frontline treatment for ER?-positive breast cancers, resistance to this drug limits its clinical efficacy. Most tamoxifen-resistant patients retain ER? expression which may support growth and progression of breast cancers. Therefore, we investigated epigenetic regulation of ER? that may provide a rationale for targeting ER? in these patients. METHODS:Expression levels of the mixed-lineage leukemia (MLL) family of proteins in tamoxifen-resistant breast cancer cells and publicly available breast cancer patient data sets were analyzed. Histone methylation levels in ER? promoter regions were assessed using chromatin immunoprecipitation. Expression levels of ER? and its target gene were analyzed using western blotting and real-time qPCR. Cell-cycle was analyzed by flow cytometry. RESULTS:The expression of MLL3 and SET-domain-containing 1A (SET1A) were increased in tamoxifen-resistant breast cancers. An MLL3 chromatin immunoprecipitation-sequencing data analysis and chromatin immunoprecipitation experiments for MLL3 and SET1A suggested that these proteins bound to enhancer or intron regions of the ESR1 gene and regulated histone H3K4 methylation status. Depletion of MLL3 or SET1A downregulated the expression level of ER? and inhibited the growth of tamoxifen-resistant breast cancer cells. Additional treatment with fulvestrant resulted in a synergistic reduction of ER? levels and the growth of the cells. CONCLUSIONS:The enhanced expression of MLL3 and SET1A in tamoxifen-resistant breast cancer cells supported the ER?-dependent growth of these cells by increasing ER? expression. Our results suggest that targeting these histone methyltransferases might provide an attractive strategy to overcome endocrine resistance.

SUBMITTER: Kim SS

PROVIDER: S-EPMC7031178 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Histone methyltransferases regulate the transcriptional expression of ERα and the proliferation of tamoxifen-resistant breast cancer cells.

Kim Seung-Su SS Lee Min-Ho MH Lee Mi-Ock MO

Breast cancer research and treatment 20200102 1

<h4>Purpose</h4>Although tamoxifen remains the frontline treatment for ERα-positive breast cancers, resistance to this drug limits its clinical efficacy. Most tamoxifen-resistant patients retain ERα expression which may support growth and progression of breast cancers. Therefore, we investigated epigenetic regulation of ERα that may provide a rationale for targeting ERα in these patients.<h4>Methods</h4>Expression levels of the mixed-lineage leukemia (MLL) family of proteins in tamoxifen-resista ...[more]

PMID: 31897900

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Project description:BackgroundPrior to the introduction of tamoxifen, high dose estradiol was used to treat breast cancer patients with similar efficacy as tamoxifen, albeit with some undesirable side effects. There is renewed interest to utilize estradiol to treat endocrine resistant breast cancers, especially since findings from several preclinical models and clinical trials indicate that estradiol may be a rational second-line therapy in patients exhibiting resistance to tamoxifen and/or aromatase inhibitors. We and others reported that breast cancer patients bearing protein kinase C alpha (PKCα)- expressing tumors exhibit endocrine resistance and tumor aggressiveness. Our T47D:A18/PKCα preclinical model is tamoxifen-resistant, hormone-independent, yet is inhibited by 17β-estradiol (E2) in vivo. We previously reported that E2-induced T47D:A18/PKCα tumor regression requires extranuclear ERα and interaction with the extracellular matrix.MethodsT47D:A18/PKCα cells were grown in vitro using two-dimensional (2D) cell culture, three-dimensional (3D) Matrigel and in vivo by establishing xenografts in athymic mice. Immunofluoresence confocal microscopy and co-localization were applied to determine estrogen receptor alpha (ERα) subcellular localization. Co-immunoprecipitation and western blot were used to examine interaction of ERα with caveolin-1.ResultsWe report that although T47D:A18/PKCα cells are cross-resistant to raloxifene in cell culture and in Matrigel, raloxifene induces regression of tamoxifen-resistant tumors. ERα rapidly translocates to extranuclear sites during T47D:A18/PKCα tumor regression in response to both raloxifene and E2, whereas ERα is primarily localized in the nucleus in proliferating tumors. E2 treatment induced complete tumor regression whereas cessation of raloxifene treatment resulted in tumor regrowth accompanied by re-localization of ERα to the nucleus. T47D:A18/neo tumors that do not overexpress PKCα maintain ERα in the nucleus during tamoxifen-mediated regression. An association between ERα and caveolin-1 increases in tumors regressing in response to E2.ConclusionsExtranuclear ERα plays a role in the regression of PKCα-overexpressing tamoxifen-resistant tumors. These studies underline the unique role of extranuclear ERα in E2- and raloxifene-induced tumor regression that may have implications for treatment of endocrine-resistant PKCα-expressing tumors encountered in the clinic.

Dataset Information

Histone methyltransferases regulate the transcriptional expression of ER? and the proliferation of tamoxifen-resistant breast cancer cells.

Publications

Histone methyltransferases regulate the transcriptional expression of ERα and the proliferation of tamoxifen-resistant breast cancer cells.

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