3,3′,4,4′-Tetrachlorobiphenyl exhibits antiestrogenic and antitumorigenic activity in the rodent uterus and mammary cells and in human breast cancer cells

Autor: Andrew McDougal, Stephen Safe, Mona Sethi Gupta, Kavita Ramamoorthy, Gulan Sun
Rok vydání: 1999
Předmět:
Cancer Research
medicine.medical_specialty
Neoplasms
Hormone-Dependent
Antineoplastic Agents
Hormonal
Progesterone receptor binding
9
10-Dimethyl-1
2-benzanthracene
Estrogen receptor
Cathepsin D
Breast Neoplasms
Transfection
Binding
Competitive
Promegestone
Rats
Sprague-Dawley
Mice
Structure-Activity Relationship
Transactivation
Mammary Glands
Animal
Genes
Reporter
Internal medicine
Tumor Cells
Cultured
medicine
Animals
Anticarcinogenic Agents
Humans
Mammary tumor
Reporter gene
Estradiol
biology
Uterus
Estrogen Antagonists
Mammary Neoplasms
Experimental
Estrogens
Organ Size
General Medicine
Aryl hydrocarbon receptor
Polychlorinated Biphenyls
Rats
Endocrinology
Gene Expression Regulation
Peroxidases
Receptors
Estrogen
Cancer cell
Cancer research
biology.protein
Female
Receptors
Progesterone
Cell Division
Zdroj: Carcinogenesis. 20:115-123
ISSN: 1460-2180
0143-3334
DOI: 10.1093/carcin/20.1.115
Popis: 3,3',4,4'-Tetrachlorobiphenyl (tetraCB) binds to the aryl hydrocarbon receptor (AhR), and several reports have demonstrated that AhR agonists exhibit antiestrogenic and antitumorigenic activities in human breast cancer cells, the rodent uterus and breast. In contrast, a recent study showed that 3,3',4,4'-tetraCB bound the estrogen receptor (ER) and exhibited ER agonist activities, and we therefore have reinvestigated the estrogenic and antiestrogenic activities of 3,3',4,4'-tetraCB. Our results showed that 3,3',4,4'tetraCB and a structurally related analog, 3,3',4,4',5-pentaCB, did not bind the mouse uterine or human ER, did not induce proliferation of MCF-7 or T47D human breast cancer cells or induce reporter gene activity in cells transfected with E2-responsive constructs derived from the creatine kinase B (pCKB) or cathepsin D (pCD) gene promoters. Moreover, 3,3',4,4'-tetraCB and 3,3',4,4',5-pentaCB did not induce an increase in uterine wet weight, peroxidase activity or progesterone receptor binding in the 21-25-day-old female B6C3F1 mouse uterus. In contrast, both compounds inhibited 17beta-estradiol (E2)-induced cell proliferation and transactivation in MCF-7/T47D cells and uterine responses in B6C3F1 mice; surprisingly inhibition of E2-induced reporter gene activity was not observed in T47D cells transfected with pCKB, and this was observed as a cell-specific response with other AhR agonists. Additionally, 3,3',4,4'-tetraCB significantly inhibited mammary tumor growth in female Sprague-Dawley rats initiated with 7,12-dimethylbenzanthracene. Our results indicate that 3,3',4,4'-tetraCB does not exhibit ER agonist activity but exhibits a broad spectrum of antiestrogenic responses consistent with ligand-mediated AhR-ER crosstalk.
Databáze: OpenAIRE
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