Androgen actions via androgen receptor promote PTEN inactivation induced uterine cancer.
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.
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.
Jaesung Peter
JP
Choi
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.
Reena
R
Desai
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.
Yu
Y
Zheng
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.
Mu
M
Yao
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.
Qihan
Q
Dong
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.
Geoff
G
Watson
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 djh@anzac.edu.au.
David J
DJ
Handelsman
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.
Ulla
U
Simanainen
D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D005260:Female; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014594:Uterine Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology
C000607144:AR protein, mouse; D000728:Androgens; D012333:RNA, Messenger; D011944:Receptors, Androgen; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
PTEN; androgen receptor; androgens; mouse; uterine cancer