Choi Jaesung Peter, Desai Reena, Zheng Yu, Yao Mu, Dong Qihan, Watson Geoff, Handelsman David J, Simanainen Ulla
ANZAC Research InstituteUniversity of Sydney, Sydney, New South Wales 2139, AustraliaDiscipline of EndocrinologyCentral Clinical School, Bosch Institute, Charles Perkins Centre, Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales 2050, AustraliaDepartment of Anatomical PathologyRoyal Prince Alfred Hospital, Sydney, New South Wales 2050, Australia.
ANZAC Research InstituteUniversity of Sydney, Sydney, New South Wales 2139, AustraliaDiscipline of EndocrinologyCentral Clinical School, Bosch Institute, Charles Perkins Centre, Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales 2050, AustraliaDepartment of Anatomical PathologyRoyal Prince Alfred Hospital, Sydney, New South Wales 2050, Australia
Endocr Relat Cancer. 2015 Oct;22(5):687-701. doi: 10.1530/ERC-15-0203.
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 ERα expression in PTENARKO compared to PTENKO uterus, while AR inactivation did not modify PTEN or P-AKT levels. Unexpectedly, while progesterone (P4) is assumed protective in uterine cancers, serum P4 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.
磷酸酶与张力蛋白同源物（Pten）单倍剂量不足的失活突变会导致考登综合征，这是一种激素依赖性生殖系统癌症的常染色体显性风险基因型。由于经由雄激素受体（AR）介导的雄激素作用会促进子宫生长并可能改变子宫癌风险，我们推测功能性AR可能会增加PTEN失活诱导的子宫癌风险。为了验证这一假设，我们比较了杂合型PTEN基因敲除（PTENKO）小鼠以及PTEN杂合型与AR完全敲除（PTENARKO）的联合杂合型雌性小鼠中PTEN基因敲除（PTENKO）诱导的子宫病变情况。在45周龄的中位年龄时，PTENARKO小鼠中出现严重宏观子宫病变的比例为21%，而PTENKO小鼠为46%，AR失活使PTENKO诱导的子宫病变显著减轻。这可能是因为与PTENKO子宫相比，PTENARKO子宫中的基质雌激素受体α（ERα）表达降低，而AR失活并未改变PTEN或磷酸化AKT（P-AKT）水平。出乎意料的是，虽然孕酮（P4）被认为对子宫癌有保护作用，但PTENKO雌性小鼠的血清P4水平明显高于野生型（WT）、AR基因敲除（ARKO）和PTENARKO雌性小鼠，这与PTENKO卵巢中有更多黄体一致。所有雌性小鼠的血清睾酮和卵巢雌二醇水平相似。因此，我们的结果表明AR失活介导了对PTENKO诱导的子宫病变的保护作用，并提示抗雄激素在子宫癌预防和治疗中可能具有潜在作用。
Zotero 插件