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Overexpression of the TGF-beta antagonist Smad7 in endometrial cancer
Sean C Dowdy1, Andrea Mariani, Monica M Reinholz
1Gynecologic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. dowdy.sean@mayo.edu
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).
Conclusion:
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.
Insights
Smad7 is overexpressed in endometrial cancers, potentially driving tumor growth by blocking TGF-beta signaling. High Smad7 expression correlates with a shorter time to recurrence in these patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- HER2/Neu activation may upregulate Smad7, which antagonizes the TGF-beta pathway.
- Inhibition of TGF-beta signaling can reduce tumor surveillance and promote cancer formation.
Purpose of the Study:
- To investigate Smad7 overexpression in endometrial cancers.
- To correlate Smad7 RNA levels with tumor grade and clinical outcomes.
Main Methods:
- Quantitative real-time PCR was used to measure Smad7 RNA expression in endometrial cancer tissues and benign controls.
- Clinical data, including time to recurrence, were collected via retrospective chart review.
Main Results:
- Smad7 transcripts were significantly elevated (over 11-fold) in endometrial tumors compared to controls.
- No significant difference in Smad7 RNA levels was observed between tumor grades 1 and 3.
- High Smad7 expression was associated with a significantly shorter median time to recurrence (30 months vs. 56.3 months).
Conclusions:
- Smad7 is upregulated in endometrial cancer and linked to poorer clinical outcomes.
- High Smad7 expression may indicate a more aggressive tumor phenotype.
- Smad7 represents a potential therapeutic target to restore TGF-beta pathway function and inhibit endometrial tumor growth.
