Epigenetic Mechanisms of Tamoxifen Resistance in Luminal Breast Cancer

Abstract

Breast cancer is one of the most common cancers and the second leading cause of cancer death in the United States. Estrogen receptor (ER)-positive cancer is the most frequent subtype representing more than 70% of breast cancers. These tumors respond to endocrine therapy targeting the ER pathway including selective ER modulators (SERMs), selective ER downregulators (SERDs) and aromatase inhibitors (AIs). However, resistance to endocrine therapy associated with disease progression remains a significant therapeutic challenge. The precise mechanisms of endocrine resistance remain unclear. This is partly due to the complexity of the signaling pathways that influence the estrogen-mediated regulation in breast cancer. Mechanisms include ER modifications, alteration of coregulatory function and modification of growth factor signaling pathways. In this review, we provide an overview of epigenetic mechanisms of tamoxifen resistance in ER-positive luminal breast cancer. We highlight the effect of epigenetic changes on some of the key mechanisms involved in tamoxifen resistance, such as tumor-cell heterogeneity, ER signaling pathway and cancer stem cells (CSCs). It became increasingly recognized that CSCs are playing an important role in driving metastasis and tamoxifen resistance. Understanding the mechanism of tamoxifen resistance will provide insight into the design of novel strategies to overcome the resistance and make further improvements in breast cancer therapeutics.

Prognostic implications of fibroblast growth factor receptor 4 polymorphisms in primary breast cancer

“…Although the mechanism of interaction between FGFR4 and ER remains unclear, it may involve regulation of FGFR4 metabolic pathways . Furthermore, approximately 70% of breast cancers are of the luminal subtype, and this high frequency suggests an association . Further work is needed to evaluate and verify the relationship between FGFR4 and ER status.…”

TET2 directs mammary luminal cell differentiation and endocrine response

“…ER-positive breast cancers consist about 80% of breast cancers. Despite the benefit of tamoxifen treatment in ER positive breast cancer, around 50% of the patients treated with adjuvant tamoxifen treatment would eventually relapse 17,44 . Resistance developed for treatment may either be intrinsic, which is present before the start of any treatment, or the resistance is acquired during the course of treatment.…”

16-Hydroxycleroda-3,13-dien-15,16-olide and N-Methyl-Actinodaphine Potentiate Tamoxifen-Induced Cell Death in Breast Cancer

“…Due to ER agonist nature, tamoxifen could reduce ER positive breast cancer growth but about 5–10% of ER negative breast cancer is sensitive to tamoxifen [ 30 ]. Moreover, tamoxifen-resistant breast cancer could be induced after long-term administration, which is a severe issue for breast cancer treatment [ 31 ]. Thus, these experiments attempted to determine whether the combination of MA or HCD with TMX can sensitize ER positive (MCF-7) and ER negative (MDA-MB231) cells to the chemotherapy drug TMX.…”