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Effect of hypophysectomy on induction of mammary cancer and CYP1 enzymes in Sprague-Dawley rats

University of British Columbia

Breast cancer is the most prevalent cancer among Canadian women and is the second leading cause of cancer-related deaths in North America. Hormonal influences including early menstruation, reproductive history, and hormone replacement therapy usage strongly affect breast cancer risk and development. In addition, hormone deprivation such as ovariectomy, hypophysectomy, and anti-estrogen therapy have been used as treatments to slow breast cancer growth. In the present study, we determined the effect of hypophysectomy on mammary carcinogenesis. Twenty intact and hypophysectornized (at 7 to 7.5 weeks) virgin Sprague-Dawley rats were treated with a single intragastric administration of 20 mg of 7,12-dimethylbenz[a]anthracene (DMBA) or an equivalent volume of corn oil between 50 to 60 days of age. None of the hypophysectomized rats developed mammary tumors at 120 days post-treatment, whereas 55% of intact rats treated with DMBA developed mammary tumors. DMBA is a polyaromatic hydrocarbon procarcinogen that requires metabolic activation by the cytochrome P450 (CYP) system and microsomal epoxide hydrolase (mEH) prior to becoming carcinogenic. To determine if CYP and mEH enzymes needed for DMBA activation are down-regulated in hypophysectomized rats, CYP1A1, CYP1A2, CYP1B1, and mEH protein levels and CYP1-mediated enzyme activities were measured in liver and mammary tissue. Immunoblot analysis showed that there were no differences in hepatic CYP1A1 and CYP1A2 levels between DMBA- or corn oil-treated intact and hypophysectomized rats. The results also showed that mammary CYP1A1, CYP1A2, and CYP1B1 from hypophysectomized and intact rats were induced by DMBA. Microsomal EH levels in the liver and mammary gland were increased in hypophysectomized rats when compared to the intact animals and DMBA treatment did not further affect mEH expression. MROD and BaP hydroxylase activities were similar in corn oil-treated hypophysectomized and intact rats and DMBA treatment increased both activities in hypophysectomized and intact rats to a similar extent. Based on the results of this study, the lack of mammary tumorigenesis in DMBA-treated hypophysectomized rats cannot be ascribed to the inability of either hepatic or mammary tissue to bioactivate DMBA.

Text

2010-01-16

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http://hdl.handle.net/2429/18178

Pharmaceutical Sciences

University of British Columbia

UBCV

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