The role of HOX genes in tamoxifen-resistant MCF7 breast cancer cells

Abstract

Endocrine therapy, such as tamoxifen and aromatase inhibitors, has been used to treat both early and advanced estrogen receptor α (ER)-positive breast cancer. Despite improvements in treatment, resistance to the current therapeutics can occur in up to one quarter of all cases and thus presents a serious therapeutic challenge. Multiple mechanisms responsible for endocrine resistance have been proposed, however, the molecular events underlying resistance to therapeutic agents are not clearly understood. Therefore, a better understanding of gene expression alterations associated with the resistance would suggest alternative regimens that overcome endocrine resistance. HOX transcription factors have recently been implicated as strong candidates to control cancer progression and metastasis. Previously, a number of strong pieces of evidence suggest that HOX genes, such as HOXB7 and HOXB13, play a critical role in the development of resistance against endocrine therapy in breast cancer. To identify other HOX genes involved in tamoxifen resistance, here we have generated in vitro model of acquired tamoxifen resistance using MCF breast cancer cells (MCF7-TamR) and analyzed expression pattern of HOX genes. MCF7-TamR cells were more resistant to tamoxifen than MCF7 cells and exhibited up-regulation of HOXB genes. Meanwhile, Kaplan-Meier analysis of the distant metastasis free survival (DMFS) for ERα-positive patients with breast cancer on adjuvant tamoxifen monotherapy showed the correlation of high HOXB expression with a poor response to tamoxifen therapy. In this report, we provide evidence that multi HOXB genes overexpression renders MCF7 cells resistant to tamoxifen. In contrast, midcluster HOXB genes knockdown in MCF7-TamR cell confer TAM sensitivity. In MCF7-TamR cells, the activation of HOXB genes was associated with histone modification with the gain of H3K9ac and loss of H3K27me3, compared to MCF7 cell. These results suggest a functional role of epigenetically regulated HOXB in the development of acquired tamoxifen resistance in breast cancer.