Genetic evidence that SMAD2 is not required for gonadal tumor development in inhibin-deficient mice.
BACKGROUND
Inhibin is a tumor-suppressor and activin antagonist. Inhibin-deficient mice develop gonadal tumors and a cachexia wasting syndrome due to enhanced activin signaling. Because activins signal through SMAD2 and SMAD3 in vitro and loss of SMAD3 attenuates ovarian tumor development in inhibin-deficient females, we sought to determine the role of SMAD2 in the development of ovarian tumors originating from the granulosa cell lineage.


METHODS
Using an inhibin alpha null mouse model and a conditional knockout strategy, double conditional knockout mice of Smad2 and inhibin alpha were generated in the current study. The survival rate and development of gonadal tumors and the accompanying cachexia wasting syndrome were monitored.


RESULTS
Nearly identical to the controls, the Smad2 and inhibin alpha double knockout mice succumbed to weight loss, aggressive tumor progression, and death. Furthermore, elevated activin levels and activin-induced pathologies in the liver and stomach characteristic of inhibin deficiency were also observed in these mice. Our results indicate that SMAD2 ablation does not protect inhibin-deficient females from the development of ovarian tumors or the cachexia wasting syndrome.


CONCLUSIONS
SMAD2 is not required for mediating tumorigenic signals of activin in ovarian tumor development caused by loss of inhibin.
Rajanahally
Saneal
S
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
Agno
Julio E
JE
Nalam
Roopa L
RL
Weinstein
Michael B
MB
Loveland
Kate L
KL
Matzuk
Martin M
MM
Li
Qinglei
Q
D028341:Activins / Q000097:blood / Q000378:metabolism; D000818:Animals; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D007265:Inhibins / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051899:Smad2 Protein / Q000235:genetics / Q000502:physiology*; D013736:Testicular Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C422362:inhibin A; D028341:Activins; D007265:Inhibins