# Estrogen Induces c-myc Transcription by Binding to Upstream ERE Element in Promoter
## 1 Introduction  
Estrogen is a steroid hormone that has critical roles in reproductive development, bone homeostasis, cardiovascular remodeling, and brain functions. However, estrogen also promotes mammary, ovarian, and endometrial tumorigenesis. Estrogen antagonists and drugs that reduce estrogen biosynthesis have become highly successful therapeutic agents for breast cancer. The three major forms of estrogen that have been reported are estrone (E1), the primary form of estrogen that the body makes after menopause, estradiol, (E2)the most potent form of estrogen in the body during reproductive years, and estriol, (E3) a form that is active during pregnancy [1]. In premenopausal conditions, estrogen is produced in the ovaries. Post menopause, adipose tissues start producing estrogen; thus, high BMI, a risk factor for breast cancer, corresponds to higher estrogen levels, which subsequently could promote cancer [2]. ER and estradiol activity are prognostic and predictive factors used in the management of BC [3]. The c-myc gene serves as a \"master regulator\" of cellular metabolism and proliferation. It stimulates various metabolic adjustments that bring about malignant transformation. Estradiol, a circulating form of estrogen, induces c-myc by ER binding. c-myc is a transcription factor that is constitutively and aberrantly expressed in over 70% of human cancers and belongs to the basic-helix-loop-helix-leucine zipper (bHLHZip) family present in the cell nucleus, where it acts to regulate cell growth, differentiation, metabolism, and death. The c-myc protein is a major transcription factor for pro-proliferative genes because it binds to enhancer box sequences (E-boxes) and recruitshistone acetyltransferases (HATs). It is known to be over-expressed in most human carcinomas due to dysregulated transcription, translation, or protein stability [4]. c-myc preferably binds to sequence-specific target sites called E-box motifs, which are found within CpG islands [5]. ERs are known to regulate gene expression to mediate the actions of estrogen that has a regulatory role in the pathology of BC [6,7]. The effects of estrogen are largely mediated by estrogen receptor (ER) \(\alpha\) and ER\(\beta\). The mechanisms underlying the aberrant expression of ER in breast cancer and other types of human tumors are complex [8]. Different isoforms of ER perform different roles in carcinogenesis. These forms interact with target genes by binding to specific estrogen response elements (EREs) in their promoters. On the other hand, ERs can indirectly interact with other domains of promoter bound-transcription factors such as activation protein 1 (AP1), nuclear factor \(\kappa\)-light-chain enhancer of activated B cells (NF-kB), or specificity protein (SP) 1 [8, 9, 10]. Estradiol, by activating the ER, makes a complex, binds to c-myc, and exerts its proliferative effect by regulating the levels of these proteins [11]. It is also known that estradiol stimulates c-myc exclusively at the transcriptional level by nuclear transcriptional activator mediation [12]. As estrogen rapidly induces the c-myc expression, it helps in the progression of the cell cycle. c-myc and ER have been used as significant soluble biomarkers in metastatic BC cells. c-myc is reported to be a vital target gene of ER, as estrogen stimulus upregulates the transcription of proto-oncogene c-myc in ER-positive BC, leading to cell proliferation [13]. Irregular estrogen signaling revamps normal metabolic pathways (including the metabolism of glucose, glutamine, and fatty acids) in cancerous cells, thus making the cell adapt to stressed conditions and stimulating cell proliferation. c-myc is involved in the regulation of glutamine metabolism through the interaction between HER2, estradiol, and ER in cells resistant to aromatase inhibitors [14]. The exact mechanism by which estradiol induces c-myc is not well-known [12].