Luteinizing hormone promotes gonadal tumorigenesis in inhibin-deficient mice.
The inhibins are secreted alpha:beta heterodimers of the TGF-beta superfamily that are mainly synthesized in Sertoli cells and granulosa cells, and are critical regulators of testicular and ovarian development and function. Mice homozygous for a targeted deletion of the inhibin alpha subunit gene (Inha(-/-)) develop sex cord-stromal tumors in a gonadotropin-dependent manner. Here, we determine the contribution of LH to gonadal tumorigenesis by generating mice deficient in both inhibins and LH. Inha(-/-)Lhb(-/-) mice have increased survival and delayed tumor progression, and these observations correlate with lower serum FSH and estradiol levels compared to Inha(-/-) controls. Double mutant testicular tumors demonstrate decreased expression of cyclin D2, while double mutant ovarian tumors have elevated expression of p15(INK4b) and trend toward higher levels of p27(Kip1). We conclude that LH is not required for tumor formation in the absence of inhibins but promotes tumor progression, likely through alterations in serum hormone levels and cell cycle regulators.
Nagaraja
Ankur K
AK
Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
Agno
Julio E
JE
Kumar
T Rajendra
TR
Matzuk
Martin M
MM
D000818:Animals; D002100:Cachexia / Q000473:pathology; D018450:Disease Progression; D004958:Estradiol / Q000097:blood; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D015972:Gene Expression Regulation, Neoplastic; D007265:Inhibins / Q000172:deficiency* / Q000378:metabolism; D008136:Longevity; D007986:Luteinizing Hormone / Q000172:deficiency / Q000378:metabolism*; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D009928:Organ Specificity; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D016019:Survival Analysis; D013577:Syndrome; D013736:Testicular Neoplasms / Q000235:genetics / Q000473:pathology*; D013739:Testosterone / Q000097:blood
C094377:inhibin-alpha subunit; D013739:Testosterone; D004958:Estradiol; D007265:Inhibins; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone