Abstract
PurposeAlthough 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.MethodsExpression 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 ERα promoter regions were assessed using chromatin immunoprecipitation. Expression levels of ERα and its target gene were analyzed using western blotting and real-time qPCR. Cell-cycle was analyzed by flow cytometry.ResultsThe 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 ERα and inhibited the growth of tamoxifen-resistant breast cancer cells. Additional treatment with fulvestrant resulted in a synergistic reduction of ERα levels and the growth of the cells.ConclusionsThe enhanced expression of MLL3 and SET1A in tamoxifen-resistant breast cancer cells supported the ERα-dependent growth of these cells by increasing ERα expression. Our results suggest that targeting these histone methyltransferases might provide an attractive strategy to overcome endocrine resistance.
Highlights
Breast cancer is the most prevalent cancer in women and is one of the leading causes of cancer death in women worldwide [1]
The expression levels of MLL1, MLL3, MLL4, SET-domain-containing 1A (SET1A), and SET1B were significantly higher in breast cancer tissues from the patients who relapsed compared with those who were relapse free (Fig. 1c) [32]
Knockdown of SET1A reduced the levels of the ERα, CCND1, and c-MYC proteins (Fig. 3b). These downregulations were more obvious in the MCF7/TAMR-1 cells compared with their parent cells (Supplementary Fig. 3a, b). These results indicate that MLL3 and SET1A are responsible for the expression of ERα and its target genes, especially in tamoxifen-resistant breast cancer cells
Summary
Breast cancer is the most prevalent cancer in women and is one of the leading causes of cancer death in women worldwide [1]. Breast Cancer Research and Treatment (2020) 180:45–54 might provide therapeutic strategies to overcome tamoxifen resistance in ER-positive breast cancers. Recent advances in genome-sequencing techniques have elucidated the wide distribution of epigenetic marks and mutations in DNA methyltransferases and histone-modifying enzymes, suggesting a direct link between alterations in the epigenome and cancer [13]. The mixed-lineage leukemia (MLL) family of proteins, MLL1, MLL2, MLL3, MLL4, SET-domain-containing 1A (SET1A), and SET1B, which all have the H3K4-methylating SET-domain, are frequently mutated in various cancers, including those of the breast, lung, large intestines, endometrium, and bladder [17]. Comprehensive DNA sequencing revealed that the genes encoding MLL3 (KMT2C) and MLL4 (KMT2D) were two of the most frequently mutated cancer driver genes [18, 19]. SET1A is overexpressed in more than 10% of all breast cancer patients and modulates the proliferation and metastasis of breast cancer cells by regulating p53 target genes, such as ARID3A, SESN1, and TP53INP1, and by regulating a group of matrix metalloproteinases [20,21,22]
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