Abstract
Abstract Estrogen receptor (ER)-positive breast cancers depend on ER signaling for growth and progression. Although tamoxifen remains the frontline treatment for such cancers, resistance to this drug limits its clinical efficacy. Nevertheless, the majority of tamoxifen-resistant patients retain ERα expression, providing a rationale for targeting ERα in these patients. Here, we found that the expression of mixed lineage leukemia (MLL) family proteins are increased in tamoxifen-resistant breast cancer cells and patients. Specifically, mixed lineage leukemia 3 (MLL3) and SET domain containing 1A (SET1A) depletion downregulated the expression of ERα protein and mRNA levels in a ER-positive breast cancer cell. Chromatin Immunoprecipitation analysis revealed that the knock-down of MLL3 and SET1A reduce the histone H3K4 methylation status in ESR1 promoter regions. We also observed the positive correlation between ERα level and MLL3/SET1A level in breast cancer clinical data sets. Importantly, MLL3 and SET1A depletion downregulated the ERα and its downstream growth-related protein levels, as well as the growth of both ER-positive and tamoxifen-resistant breast cancer cells. Likewise, MLL3 and SET1A knockdown decreased the proportion of cells entering the cell cycle. Additional fulvestrant treatment resulted in synergistic reduction of ERα levels and growth of the tamoxifen-resistant breast cancer cells. Thus, enhanced expression of MLL3 and SET1A in tamoxifen-resistant breast cancer cells supported ERα-dependent growth of breast cancer cells, suggesting that MLL3 SET1A might provide an attractive target for overcoming endocrine resistance. Citation Format: Seungsu Kim, Min-Ho Lee, Mi-Ock Lee. Enhanced expression of histone methyltransferases increase ERα expression in tamoxifen-resistant breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4320.
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