"Investigating The Role of Key Non-coding RNA(s) in Breast Cancer Patients and Their Possible Crosstalk With Chromatin Remodeling Machinery"

Breast cancer is considered as one of the most frequent malignancies in women worldwide and one of the leading cause of death among women globally. Even with remarkable advances in diagnosis and therapy, the prognosis of breast cancer patients remains disappointing[1][2]. Breast cancer is a highly heterogeneous disease that is classified into four subtypes based on the expression of certain hormonal receptors as estrogen receptor ER, progesterone receptor PR and human epidermal growth factor receptor HER2[2]. The following are the four subtypes of breast cancer: Luminal A tumors are characterized by the presence of ER and/or PR and the absence of HER2, Luminal B tumors are of higher grade and worse prognosis compared to Luminal A, they are ER positive and can be PR negative and have a high expression of Ki67 (greater than 20%), the HER2-positive group constitutes 10-15% of breast cancers and is characterized by high HER2 expression with absence of ER and PR and Triple-negative breast cancer which lack the expression of the previous three receptors[3][4].

Epigenetics regulation of gene expression is the alteration in gene expression function without changing the nucleotide sequence. Both activation and inactivation of cancer-associated genes can occur by epigenetic mechanisms. The major players in epigenetic mechanisms of gene regulation are DNA methylation, histone modification, chromatin remodelers , and noncoding RNA expression[5].

Histone modifications are one of the important regulators of chromatin structure which is very crucial for gene expression as it defines accessibility of DNA for transcriptional regulators, affects gene expression, and influences vital cellular processes [6].

Histone modifications can recruit transcription factors, chromatin remodelers, and chromatin structural proteins so contribute to the formation and maintenance of active or repressive chromatin state[6]. The most important histone modifications are: lysine acetylation, lysine and arginine methylation, serine/threonine/tyrosine phosphorylation, and serine/threonine ubiquitylation [6]. Many of histone modification enzymes are frequently mutated in different types of cancer by example: EHMT2 (G9A) encodes a methyltransferase that methylates lysine residues of histone H3, Methylation of H3 at lysine 9 by this protein results in recruitment of additional epigenetic regulators and repression of transcription. The histone methyltransferase G9a is well-documented for its implication in neoplastic growth[7]. Another example on histone modification enzymes is KMT5B (SUV420H1) a methyl transferase enzyme that catalyzes the deposition of H4k20me mark, a repressive mark and is believed to have a tumor suppressor role in many cancer types[8].

The chromatin structure can also be regulated by chromatin remodelers' complexes, they are four conserved families of ATP-dependent chromatin remodelers in mammals (CHD), (ISWI), (INO80), and (SWI/SNF), and are involved in most essential cell processes [9].