Role of androgens via AR in PTEN inactivation induced uterine pathology. (#12)
Inactivating mutations in the phosphatase and tensin homolog (PTEN) gene cause Cowden syndrome (CS), an autosomal dominant genetic disorder which increases the risk of hormone dependent reproductive cancers including breast and uterus. We have demonstrated experimentally that androgen action via androgen receptor (AR) inhibits hormone dependent growth and carcinogenesis of the mouse mammary gland. Therefore, we hypothesized that androgens via AR may also reduce PTEN inactivation induced uterine endometriosis.
Our objective was to determine the effect of AR inactivation on PTEN inactivation induced uterine pathology. To test our hypothesis, development of uterine pathology was compared between wild-type (WT), heterozygous PTEN knockout (PTENKO) and combined heterozygous PTEN and complete AR knockout (PTENARKO) female mice (Cre/LoxP system; global deletion). Serum and ovarian steroids were analyzed using liquid chromatography tandem mass spectrometry.
Against our hypothesis PTEN inactivation induced uterine pathology was significantly reduced by AR inactivation. While 37% (19 out of 52) of PTENKO mice developed macroscopic uterine abnormalities, only 9% (2 out of 23) of PTENARKO had abnormal uteri as detected at termination with median age of 45 weeks (Pearson Chi-square, p=0.013). No uterine abnormalities were found in WT females (n=32). The macroscopic uterine abnormalities were manifest as significantly increased uterine weight in PTENKO [1690±334mg (mean±SE); n=52] females compared to WT (156±23mg; n=32) and PTENARKO (516±163mg; n=23) (p≤0.007).
Unexpectedly, serum progesterone (P4) was significantly (p=0.001) increased in PTENKO (17±2.2ng/ml; n=28) females compared to WT (4.4±0.7ng/ml; n=18) and PTENARKO (5.4±1.2ng/ml; n=16). Increased circulating P4 in PTENKO could arise from ovarian secretions, as intra-ovarian P4 was non-significantly increased in PTENKO (10.8±4.7ng/mg; n=4) females compared to WT (2.8±0.3ng/mg; n=4) and PTENARKO (3.1±1ng/mg; n=5) (p=0.453).
In conclusion, the increased circulating P4 in PTENKO was not able to protect against uterine pathology. However, AR inactivation protected against PTEN inactivation induced uterine pathology a well as increases in circulating P4. Therefore, further analysis on mechanism(s) involved as well as uterine specific effects of AR are warranted.