Abstract
Breast cancer is currently the most frequent, fatal cancer of women in western countries. While estrogens have a widely understood involvement in breast cancer, a significant but not yet fully understood role for androgens has also been suggested. The principal androgen, testosterone, is the obligate steroidal precursor of estradiol, but can equally be metabolized into dihydrotestosterone, a more potent, pure androgen. Both androgens exert their distinctive biological effects via the androgen receptor, which is coexpressed with estrogen receptor alpha in 80 to 90% of breast cancers. The hormonal control of breast development and pathology has been examined experimentally through the use of animal models, notably mice and rats. This review summarizes the data from experimental rodent models on the effects of androgens in experimental breast cancer, aiming to address the importance of androgens and the androgen receptor in the origins and pathogenesis of breast cancers, as well as to discuss potential biomarker and therapeutic opportunities arising from novel insights based on the experimental research.
Highlights
Breast cancer is currently among the most frequent and fatal cancers afflicting women worldwide
To integrate the estrogen-independent mammary tumors in mice into a more estrogen-sensitive framework, specific estrogen receptor (ER)-positive mammary tumor mouse models have been developed and we found that DMBA generates both ERα-positive and ERα-negative tumors in mice [1]
Using an androgen receptor knockout (ARKO) androgen-insensitive female mouse model combined with DMBA chemical carcinogenesis, we demonstrated that the onset of palpable mammary tumors was significantly faster in ARKO females compared with wild-type female mice [1], supporting the inhibitory role of AR-mediated androgen actions in mammary carcinogenesis
Summary
Breast cancer is currently among the most frequent and fatal cancers afflicting women worldwide. Using an androgen receptor knockout (ARKO) androgen-insensitive female mouse model (expressing a mutated, inactive AR) combined with DMBA chemical carcinogenesis, we demonstrated that the onset of palpable mammary tumors was significantly faster in ARKO females compared with wild-type female mice (median time, 22 weeks vs 34 weeks, respectively) [1], supporting the inhibitory role of AR-mediated androgen actions in mammary carcinogenesis This observation predicts that otherwise healthy women who are heterozygous for the functional and inactive AR alleles (for example, mothers of children with androgen insensitivity) could be at increased risk of breast cancer, this prediction remains to be tested. Androgens and genetically modified mouse breast cancer models In our studies, androgen-insensitive female mice (global ARKO model) have increased susceptibility to DMBAinduced mammary tumors, which demonstrates direct mammary gland-specific effects of androgens acting via the AR [1]. While only few studies have so far utilized the ARKO mouse models, in the future these models (both global and cell-specific ARKO) combined with various transgenic experimental breast cancer models may be uniquely enlightening when exploring the cell-specific role of AR as well as the influence of AR-mediated androgen actions on specific carcinogenic pathways
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