Androgen resistance in female mice increases susceptibility to DMBA-induced mammary tumors.

Abstract

Hormones, notably estrogens, are pivotal in the origins of breast cancer but androgenic effects, while supported by persistence of AR expression in breast cancers, remain controversial. This study determined the role of the androgen actions via androgen receptor (AR) in experimental mammary cancer. Androgen-resistant female and male mice (ARKO) were generated using Cre/loxP technique and featured a global AR inactivation. The effect of AR inactivation and influence of genetic background on 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumorigenesis was confirmed using two separate ARKO models with different genetic backgrounds. The onset of palpable mammary tumors was significantly faster in ARKO females (median time 22 vs 34 weeks, respectively; (p = 0.0024; multivariate Cox regression) compared to WT and independent of the mouse genetic background. The cumulative incidence at 9 months was 81 ± 10% [mean ± SE] for ARKO compared to 50 ± 13% in WT females. The increased DMBA susceptibility of ARKO females was associated with a higher epithelial proliferation index but not with major structural or receptor (estrogen or progesterone) expression differences between the virgin WT or ARKO female mammary glands. AR inactivation allowed substantial ductal extension in ARKO males while WT males displayed only rudimentary epithelial branches or complete regression of epithelial structures. Yet, DMBA did not induce epithelial mammary tumors in WT or ARKO males, demonstrating that AR inactivation alone is insufficient to promote mammary tumors. These results demonstrate that AR inactivation accelerates mammary carcinogenesis in female mice exposed to the chemical carcinogen DMBA regardless of mouse genetic background but require prior exposure to endogenous ovarian hormones.

• Authors: Ulla Simanainen, Yan Ru Gao, Kirsty A Walters, Geoff Watson, Reena Desai, Mark Jimenez, David J Handelsman
• Journal: Hormones & cancer (Horm Cancer) Vol. 3 Issue 3 Pg. 113-24 (Jun 2012) ISSN: 1868-8500 [Electronic] United States
• PMID: 22370991 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Androgens
• Gonadotropins, Pituitary
• Receptors, Androgen
• Testosterone
• 9,10-Dimethyl-1,2-benzanthracene

Topics

• 9,10-Dimethyl-1,2-benzanthracene
• Androgens (metabolism)
• Animals
• Cell Proliferation
• Cell Transformation, Neoplastic (genetics, metabolism)
• Epithelial Cells (metabolism, pathology)
• Female
• Genetic Predisposition to Disease
• Gonadotropins, Pituitary (blood)
• Male
• Mammary Neoplasms, Experimental (chemically induced, etiology, genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Receptors, Androgen (genetics, metabolism)
• Testosterone (blood)