Epigenetics and environment in breast cancer: New paradigms for anti-cancer therapies

Abstract

Breast cancer remains the most frequently diagnosed cancer in women worldwide. Delayed presentation of the disease, late stage at diagnosis, limited therapeutic options, metastasis, and relapse are the major factors contributing to breast cancer mortality. The development and progression of breast cancer is a complex and multi-step process that incorporates an accumulation of several genetic and epigenetic alterations. External environmental factors and internal cellular microenvironmental cues influence the occurrence of these alterations that drives tumorigenesis. Here, we discuss state-of-the-art information on the epigenetics of breast cancer and how environmental risk factors orchestrate major epigenetic events, emphasizing the necessity for a multidisciplinary approach toward a better understanding of the gene-environment interactions implicated in breast cancer. Since epigenetic modifications are reversible and are susceptible to extrinsic and intrinsic stimuli, they offer potential avenues that can be targeted for designing robust breast cancer therapies.

Keywords: DNA methylation; breast cancer; chromatin modification; environment; epigenetics; metabolism; therapies.

Figure 1

Classification of Breast Cancer (A) Breast showing the different tissue types consisting of duct, lobe, lobules, nipples, and fatty tissue. (B) Cross-sectional view of mammary duct, consisting of basal cells and luminal cells. Breast cancer arising from the luminal or basal cells can be further characterized based on the expression of different hormone receptors. (C) Based on the expression of ER, PR, HER2, and proliferation status as assessed by Ki67, different molecular subtypes of breast cancer have been identified that have distinct prognostic features and response to therapies (3).

Figure 2

Overview of Key Epigenetic Events in Breast Cancer. Mechanisms for epigenetic alterations in breast cancer are shown focusing on two major players that include the methylation of DNA and the modification of histone proteins. Hypomethylation of oncogenes and hypermethylation of tumor suppressor genes is an important epigenetic phenomenon in breast cancer that affects various cellular processes of proliferation, apoptosis, migration, invasion, drug resistance, etc. Post translation modifications made to histone proteins impact gene expression by altering the chromatin structure towards open or closed conformation. Histone methylation of lysine is implicated in both transcriptional activation and repression depending on the methylation site that constitutes the various histone marks/code.

Figure 3

Epigenetic Targets and other combined inhibitors for breast cancer therapies under clinical trial. Data adapted from (154). Star (*) represents the specific epigenetic agent.