Androgen actions via androgen receptor promote PTEN inactivation induced uterine cancer
Androgen actions via androgen receptor promote PTEN inactivation induced uterine cancer
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DOI：
10.1530/erc-15-0203
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发表时间：
2015-10-01
影响因子：
3.9
通讯作者：
Simanainen, Ulla
中科院分区：
文献类型：
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作者：
Choi, Jaesung (Peter);Desai, Reena;Simanainen, Ulla
单倍不足的失活磷酸酶和紧张素同源物（Pten）突变导致考登综合征，一种激素依赖性生殖癌的常染色体显性风险基因型。由于雄激素受体（AR）介导的雄激素作用支持子宫生长并可能改变子宫癌的风险，我们假设功能性AR可能增加PTEN失活诱导的子宫癌。为了验证这一假设，我们比较了PTEN基因敲除（PTENKO）在杂合PTENKO和杂合PTEN和AR基因完全敲除（PTENARKO）的雌性小鼠中引起的子宫病理。AR失活显著降低了PTENKO诱导的子宫病理，在中位年龄45周时，PTENARKO患者中有21%出现严重的宏观子宫病理，而PTENKO患者中有46%出现严重的宏观子宫病理。这可能是由于与PTENKO子宫相比，PTENARKO子宫中基质ER α表达减少，而AR失活并未改变PTEN或P-AKT水平。出乎意料的是，虽然孕酮（P-4）被认为对子宫癌有保护作用，但PTENKO女性的血清P-4明显高于WT、ARKO和PTENARKO女性，这与PTENKO卵巢中更多的黄体一致。血清睾酮和卵巢雌二醇在所有女性中相似。因此，我们的研究结果证明了AR失活介导的对PTENKO诱导的子宫病理的保护作用，并提示抗雄激素在子宫癌预防和治疗中的潜在作用。
Haploinsufficient inactivating phosphatase and tensin homolog (Pten) mutations cause Cowden syndrome, an autosomal dominant risk genotype for hormone dependent reproductive cancers. As androgen actions mediated via the androgen receptor (AR) supports uterine growth and may modify uterine cancer risk, we hypothesized that a functional AR may increase PTEN inactivation induced uterine cancer. To test the hypothesis, we compared the PTEN knockout (PTENKO) induced uterine pathology in heterozygous PTENKO and combined heterozygous PTEN and complete AR knockout (PTENARKO) female mice. PTENKO induced uterine pathology was significantly reduced by AR inactivation with severe macroscopic uterine pathology present in 21% of PTENARKO vs 46% of PTENKO at a median age of 45 weeks. This could be due to reduced stroma ER alpha expression in PTENARKO compared to PTENKO uterus, while AR inactivation did not modify PTEN or P-AKT levels. Unexpectedly, while progesterone (P-4) is assumed protective in uterine cancers, serum P-4 was significantly higher in PTENKO females compared to WT, ARKO, and PTENARKO females consistent with more corpora lutea in PTENKO ovaries. Serum testosterone and ovarian estradiol were similar between all females. Hence, our results demonstrated AR inactivation mediated protection against PTENKO induced uterine pathology and suggests a potential role for antiandrogens in uterine cancer prevention and treatment.