Conditional deletion of Smad1 and Smad5 in somatic cells of male and female gonads leads to metastatic tumor development in mice.
The transforming growth factor beta (TGFbeta) family has critical roles in the regulation of fertility. In addition, the pathogenesis of some human cancers is attributed to misregulation of TGFbeta function and SMAD2 or SMAD4 mutations. There are limited mouse models for the BMP signaling SMADs (BR-SMADs) 1, 5, and 8 because of embryonic lethality and suspected genetic redundancy. Using tissue-specific ablation in mice, we deleted the BR-SMADs from somatic cells of ovaries and testes. Single conditional knockouts for Smad1 or Smad5 or mice homozygous null for Smad8 are viable and fertile. Female double Smad1 Smad5 and triple Smad1 Smad5 Smad8 conditional knockout mice become infertile and develop metastatic granulosa cell tumors. Male double Smad1 Smad5 conditional knockout mice are fertile but demonstrate metastatic testicular tumor development. Microarray analysis indicated significant alterations in expression of genes related to the TGFbeta pathway, as well as genes involved in infertility and extracellular matrix production. These data strongly implicate the BR-SMADs as part of a critical developmental pathway in ovaries and testis that, when disrupted, leads to malignant transformation.
Pangas
Stephanie A
SA
Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. spangas@bcm.edu
Li
Xiaohui
X
Umans
Lieve
L
Zwijsen
An
A
Huylebroeck
Danny
D
Gutierrez
Carolina
C
Wang
Degang
D
Martin
James F
JF
Jamin
Soazik P
SP
Behringer
Richard R
RR
Robertson
Elizabeth J
EJ
Matzuk
Martin M
MM
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D005260:Female; D005298:Fertility; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006106:Granulosa Cell Tumor / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009362:Neoplasm Metastasis / Q000473:pathology*; D010053:Ovary / Q000166:cytology / Q000378:metabolism*; D012707:Sertoli Cell Tumor / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051898:Smad1 Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051902:Smad5 Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051904:Smad8 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013736:Testicular Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013737:Testis / Q000166:cytology / Q000378:metabolism*
D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D051904:Smad8 Protein; C491621:Smad9 protein, mouse