Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells

Journal Article · Sun Nov 01 00:00:00 EDT 2009 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.07.013· OSTI ID:21344775

Spink, Barbara C ^[1]; Bennett, James A ^[2]; Pentecost, Brian T ^[1]; Lostritto, Nicole ^[2]; Englert, Neal A ^[1]; Benn, Geoffrey K; Goodenough, Angela K ^[1]; Turesky, Robert J ^[1]

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1. Laboratory of Molecular Toxicology, Wadsworth Center, New York State Department of Health, Albany, NY 12201-0509 (United States)
2. Center for Immunology and Microbial Diseases, Albany Medical College, Albany, NY 12208-3479 (United States)

The cumulative exposure to estrogens is an important determinant in the risk of breast cancer, yet the full range of mechanisms involving estrogens in the genesis and progression of breast cancer remains a subject of debate. Interactions of estrogens and environmental toxicants have received attention as putative factors contributing to carcinogenesis. Mechanistic studies have demonstrated interactions between estrogen receptor alpha (ERalpha) and the aryl hydrocarbon receptor (AhR), with consequences on the genes that they regulate. Many studies of ERalpha and AhR-mediated effects and crosstalk between them have focused on the initial molecular events. In this study, we investigated ERalpha- and AhR-mediated effects in long-term estrogen exposed (LTEE) MCF-7 human breast cancer cells, which were obtained by continuous culturing for at least 12 weeks in medium supplemented with 1 nM of 17beta-estradiol (E{sub 2}). With these LTEE cells and with parallel control cells cultured without E{sub 2} supplementation, we performed an extensive study of cytochrome P450 (CYP) induction, carcinogen bioactivation, global gene expression, and tumorigenicity in immunocompromised mice. We found that LTEE cells, in comparison with control cells, had higher levels of AhR mRNA and protein, greater responsiveness for AhR-regulated CYP1A1 and CYP1B1 induction, a 6-fold higher initial level of benzo(a)pyrene-DNA adducts as determined by liquid chromatography tandem mass spectrometry, marked differences in the expression of numerous genes, and a higher rate of E{sub 2}-dependent tumor growth as xenografts. These studies indicate that LTEE causes adaptive responses in MCF-7 cells, which may reflect processes that contribute to the overall carcinogenic effect of E{sub 2}.

• OSTI ID: 21344775
• Journal Information: Toxicology and Applied Pharmacology, Vol. 240, Issue 3; Other Information: DOI: 10.1016/j.taap.2009.07.013; PII: S0041-008X(09)00295-6; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS
CARCINOGENESIS
CARCINOGENS
ESTRADIOL
GENES
GENETIC EFFECTS
MAMMARY GLANDS
MEN
NEOPLASMS
ANIMALS
BIOLOGICAL EFFECTS
BODY
DISEASES
ESTRANES
ESTROGENS
GLANDS
HORMONES
HYDROXY COMPOUNDS
MALES
MAMMALS
MAN
ORGANIC COMPOUNDS
ORGANS
PATHOGENESIS
PRIMATES
STEROID HORMONES
STEROIDS
VERTEBRATES