Overexpression of the TGF-beta antagonist Smad7 in endometrial cancer.
OBJECTIVE
We have shown that HER2/Neu may activate the Smad7 promoter in endometrial, ovarian, and breast cancer cell lines. Elevated Smad7 levels could then antagonize the TGF-beta pathway, leading to a reduction in tumor surveillance and potential cancer formation. Our aim was to determine if Smad7 was in fact overexpressed in endometrial cancers and whether Smad7 RNA levels correlated with tumor grade or clinical endpoints.


METHODS
Snap-frozen endometrial cancer specimens from 16 patients with grade 1 disease and 23 patients with grade 3 disease were obtained. Additionally, the endometrium from 18 patients who underwent hysterectomy for benign indications was collected as a control. RNA was extracted and subjected to quantitative real-time PCR to determine the degree of Smad7 RNA expression. Clinical outcomes including time to recurrence were recorded through retrospective chart review.


RESULTS
Smad7 transcripts in the tumors were over 11-fold elevated on average than in controls (P < 0.001). There was no significant difference in Smad7 RNA between grades 1 and 3 tumors. For the 19 patients who recurred, median time to recurrence was 56.3 months for those with low Smad7 expression versus 30 months for those with high Smad7 expression (P < 0.004).


CONCLUSIONS
Smad7 appears to be upregulated in endometrial cancers compared to normal endometrium. Furthermore, high Smad7 gene expression was associated with a shorter time to recurrence. Given that many endometrial cancers have been shown to be TGF-beta-unresponsive, Smad7 should be investigated as a potential target to restore TGF-beta responsiveness and limit tumor growth.
Dowdy
Sean C
SC
Gynecologic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. dowdy.sean@mayo.edu
Mariani
Andrea
A
Reinholz
Monica M
MM
Keeney
Gary L
GL
Spelsberg
Thomas C
TC
Podratz
Karl C
KC
Janknecht
Ralf
R
D003598:Cytoskeletal Proteins / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008875:Middle Aged; D010766:Phosphorylation; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D051899:Smad2 Protein; D051900:Smad3 Protein; D051906:Smad7 Protein; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D051176:beta Catenin
D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D012334:RNA, Neoplasm; D018719:Erb-b2 Receptor Tyrosine Kinases; D051899:Smad2 Protein; D051900:Smad3 Protein; D051906:Smad7 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D051176:beta Catenin; C495270:CTNNB1 protein, human; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497806:SMAD7 protein, human