The role of estrogen in the initiation of breast cancer

Abstract

Estrogens are considered to play a major role in promoting the proliferation of both the normal and the neoplastic breast epithelium. Their role as breast carcinogens has long been suspected and recently confirmed by epidemiological studies. Three major mechanisms are postulated to be involved in their carcinogenic effects: stimulation of cellular proliferation through their receptor-mediated hormonal activity, direct genotoxic effects by increasing mutation rates through a cytochrome P450-mediated metabolic activation, and induction of aneuploidy. Recently it has been fully demonstrated that estrogens are carcinogenic in the human breast by testing in an experimental system the natural estrogen 17β-estradiol (E 2 ) by itself or its metabolites 2-hydroxy, 4-hydroxy, and 16-a-hydroxyestradiol (2-OH-E 2, 4-OH-E 2, and 16-α-OH E 2 ) respectively, by inducing neoplastic transformation of human breast epithelial cells (HBEC) MCF10F in vitro to a degree at least similar to that induced by the chemical carcinogen benz(a)pyrene (BP). Neither TAMOXYFEN (TAM) nor ICI-182,780 abrogated the transforming efficiency of estrogen or its metabolites. The E 2 induced expression of anchorage independent growth, loss of ductulogenesis in collagen, invasiveness in Matrigel, is associated with the loss of 9p11-13 and only invasive cells that exhibited a 4p15.3-16 deletion were tumorigenic. Tumors were poorly differentiated ER-α and progesterone receptor negative adenocarcinomas that expressed keratins, EMA and E-cadherin. The E 2 induced tumors and tumorderived cell lines exhibited loss of chromosome 4, deletions in chromosomes 3p12.3-13, 8p11.1-21, 9p21-qter, and 18q, and gains in 1p, and 5q15-qter. The induction of complete transformation of the human breast epithelial cell MCF-10F in vitro confirms the carcinogenicity of E 2 , supporting the concept that this hormone could act as an initiator of breast cancer in women. This model provides a unique system for understanding the genomic changes that intervene for leading normal cells to tumorigenesis and for testing the functional role of specific genomic events taking place during neoplastic transformation. Keywordsestrogen; invasiveness; CGH; breast cancer 1.IntroductionBreast cancer is a malignancy whose dependence on ovarian function was first recognized through the regression of both advanced cancer (1) and metastatic disease (2) induced by oophorectomy in premenopausal women. Ulterior correlation of ovarian function with estrogen (1) To whom correspondence must be addressed: Jose Russo, M.D., F.C. A.P. Director, Breast Cancer Research Laboratory, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA, Phone: 215-728-4782, Fax: 215-728-2180, E-Mail: j_russo@fccc.edu Grant Numbers and Sources of support: This work was supported by the U.S. Army Medical and Research Materiel Command under grants DAMD17-00-1-0247 and DAMD17-03-1-0229.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a servi...

The 4-hydroxyestrone: Electron emission, formation of secondary metabolites and mechanisms of carcinogenesis

“…At higher 17β-E2 concentrations, the metabolites: 2-hydroxyestrone, 2-hydroxyestradiol, 2-hydroxyestriol, 4-hydroxyestrone and 4-hydroxyestradiol caused significant inhibition of the cell proliferation. Recent studies confirmed the previous findings that estrogens play a major role in promoting the proliferation of both, normal as well as the neoplastic breast epithelium cells [6,7]. It has been also found that patients with fibrocystic diseases are at elevated risk for developing breast cancer.…”

“…Based on experimental evidence, 17β-estradiol (17β-E2) is blamed for the initiation of breast cancer [1][2][3][4][5][6][7][8]. Almost all of its A-ring metabolites exhibit two different biological actions on cell proliferation: at low concentrations (10 −8 -10 −6 mol/L) 17β-E2 stimulates, but at higher concentrations (>10 −5 mol/L) it inhibits the proliferation of cultured cells [3].…”

A genome-wide study of the repressive effects of estrogen receptor beta on estrogen receptor alpha signaling in breast cancer cells

“…This implies a double negative feedback loop for ERa at both the transcript (downregulation of wt variant) and protein level (upregulation of dominant-negative variant), whereas ERb opposes ERa by downregulating its wt variant but does not induce the dominant negative ERa variant. In addition, we observe that LRH-1 (NR5A2), which controls the expression of aromatase, is upregulated by ERa and opposed by ERb, thus affecting local estrogen production, which for breast tumors in vivo is thought to be the most important estrogen source (Russo and Russo, 2006).…”

Exposure to estrogen and ionizing radiation causes epigenetic dysregulation, activation of mitogen-activated protein kinase pathways, and genome instability in the mammary gland of ACI rats

“…13 More importantly, women with elevated estrogen levels are considered to be a high-risk group for breast cancer development 14,15 and are likely to be exposed to diagnostic radiation procedures more frequently. Similarly, many patients with estrogen-induced breast cancer undergo radiation treatment and are exposed to relatively high X-ray doses to the healthy breast.…”