Regulation of Breast Cancer by DNA Methylation and Histone Mark Modulations

Abstract

Breasts are vital accessory organs of the female reproductive system, which indirectly impart folliculogenesis. Hence, disorder of breast function affects reproduction. One of the biggest threats of breast function disorders is breast cancer. Genetic susceptibility in breast cancer is characterized by the presence of single nucleotide polymorphisms (SNPs) and copy number variations (CNVs). Notably, the extent of heterogeneity and types of breast cancers can’t be explained by genetic alterations. The prevailing views based on molecular mechanisms implicates that aberrant epigenetic modifications of chromatin (DNA & histones) are the major culprits for tumor development and cancer progressions, including breast cancer. The progression from benign tumor to malignant cancer is characterized by differential modulations of genes by DNA methylation, histone modification and RNA-interference. This talk highlights the DNA methylation and histone modifications driven progression of breast cancer. The mammary gland is a highly evolved and specialized organ present in pairs, one on each side of the anterior chest wall. The organ's primary function is to secrete milk. Though it is present in both sexes, it is well developed in females and rudimentary in males. It is also a vital accessory organ of the female reproductive system. For example, in all mammals’ lactation (precisely, the suckling stimulus) induces a period of infertility designed to provide the optimal birth spacing for survival of the offspring. The time period of lactational infertility depends on the sucking activity of the offspring. Suckling disrupts the normal pulsatile pattern of hypothalamic gonadotrophin releasing hormone (GnRH)2 secretion resulting in reduced Luteinizing hormone (LH) secretion from the pituitary. Secretion of follicle stimulating hormone (FSH) returns to its normal cyclic pattern early in lactation and ovarian follicles may develop under its influence. However, until suckling declines, the follicles fail to secrete amounts of estradiol adequate to stimulate an LH surge for ovulation. Breast cancer (BC) is the leading cause of morbidity and mortality in women across worldwide (Sengupta et al., 2016). The heterogeneity in this disease is characterized by spectrum of histological subtypes, sensitivity in treatment modalities and clinicopathological outcomes among different patients. The classical system of classification is based on tumour size, histological grades, lymph node metastases, patient’s age and prevalence of hormonal receptors. There are 17 different subtypes of BC identified based on histological grading by World Health Organization (Bocker, 2002; Weigelt et al., 2008), depending upon discrete histological grading, prognosis and target specific response to chemotherapy. Majority of breast cancer were categorized under invasive ductal (IDC) (50-80%) and lobular carcinoma (5-15%) and 10 year survival rate was observed in 35-50% of the patients. Quite often, these tumours offer resistance to drug treatment and the disease relapses. BC are sub-grouped as, estrogen (ER+), progesterone (PR+) and human epidermal growth factor (HER2+) based on the presence of hormonal receptors, The absence of these receptors encompasses tumor into triple-negative breast cancer (ER/PR/HER2−) (Rakha and Ellis, 2011; Eroles et al., 2012; Prat et al., 2015). Approximately 75% of BC have been identified to be ER/PR+. These ER+ tumours express genes encodes for proteins responsible for the proliferation of luminal epithelial cells and are grouped into luminal A and B subclass. While luminal A is characterised by increased expression of CK8, CK18, LIV1, FOXA1, GATA3, BLC2, erB3 and erB4 genes (van 't Veer et al., 2002; Carey et al., 2006; Carey, 2010; Geyer et al., 2012); luminal B shows elevated expression of GGH, vMYB, LAPTMB4, NSEP1and CCNE1 genes (Berquin et al., 2005; Loi et al., 2009; Reis-Filho et al., 2010). HER2 positive cells are characterised by high expression of PI3, AKT, RAS, RAF, MEK, and ERK genes (Moasser, 2007; Seo et al., 2015; Du et al., 2018; Nokin et al., 2019). However, triple-negative BC is characterized with increased expression of BRCA1, Ki67, TP53, EGFR and P-Cadherin genes (Toyama et al., 2008; Ribeiro and Paredes, 2014). The heterogeneity within this subtype is a consequence of distinct genetic aberrations and histological morphology, leading to its stratification into high and low grade, respectively. While low-grade TNBC is characterised by salivary-gland breast tumors and papillary carcinoma, high-grade TNBC is underpinned by somatic genomic landscape. The transition from low to high-grade TNBC occurs at differential rate. Moreover, the histological difference gradation of low and high-grade TNBC is significant in relevance to therapeutic implications (Geyer et al., 2017). DNA methylation (at the cytosine 5-carbon position in the context of CpG-sequences densely packed, CpG-island, on the gene promoters) mediated repression of various genes in breast cancer progression are well documented during the last thirty years (Ottaviano et al., 1994; Pakneshan et al., 2004; Parbin et al., 2016; Park et al., 2011; Patra et al., 2008).