10 Feb What Makes Growth Factor Switch From Tumor Suppressor to Tumor Promoter?
MedicalResearch.com Interview with:
Dihua Yu, M.D., Ph.D.
Hubert L. & Olive Stringer Distinguished Chair in Basic Science
Professor and Deputy Chair
Department of Molecular and Cellular Oncology
Co-Director, Center of Biological Pathways
The Univ. Texas MD Anderson Cancer Center Houston, TX 77030
Medical Research: What is the background for this study?
Dr. Yu: Transforming growth factor β (TGF-β) functions as a tumor suppressor in premalignant cells but may also function as a metastasis promoter in cancer cells. This study aimed to understand how the growth factor makes this switch between tumor suppressor to tumor promoter.
Medical Research: What are the main findings?
Dr. Yu: We reported that 14-3-3ζ overexpression (14-3-3ζ+++) can switch TGF-β’s function from tumor suppressor to metastasis promoter by changing Smad partners. Specifically, 14-3-3ζ+++ led to destabilization of p53, a Smad determinant in pre-malignant cells, thus disrupting p53/Smad complex, and consequently inhibiting TGF-β-induced p21 expression and cytostatic function in non-malignant human mammary epithelial cells (HMECs). On the contrary, 14-3-3ζ+++ stabilized Gli2, a Smad partner in cancer cells, and Gli2 complexed with Smads to promote TGF-β-induced parathyroid hormone-related protein (PTHrP) expression, which enhanced breast cancer bone metastasis. Remarkably, both transcriptomic analyses and clinical pathology data indicated that 14-3-3ζ+++ is associated with the loss of TGF-β’s tumor suppressor function and the gain of its metastasis promoter function by changing contextual partners of Smads. Taken together, we have identified 14-3-3ζ as a novel molecular switch of TGF-β’s function by altering Smad partners from p53 in pre-malignant cells to Gli2 in cancer cells. The study provided important answers to the long-standing questions of how and when TGF-β switches its functional roles from a tumor suppressor to a metastasis promoter. The findings established a scientific base for a new strategy of selectively targeting TGF-β signaling in cancer by inhibiting the cancer-specific Smad partner without blocking TGF-β’s tumor suppressor function in normal tissues.
Medical Research: What should clinicians and patients take away from your report?
Dr. Yu: The crucial role of TGF-β in cancer and other diseases has motivated a lot of efforts on developing TGF-β-targeting therapeutics, some of which have been tested in the clinic (Akhurst and Hata, 2012). In limited phase I and II trials for treating cancers that generally overexpress TGF-β, some patients with late-stage cancers received a marginal benefit from TGF-β inhibitors (Bogdahn et al., 2011). A major obstacle for effective TGF-β-targeting therapies has been the complex nature and opposing roles of TGF-β in different stages of cancer development. Thus, understanding the molecular mechanism by which TGF-β switches its role could guide more effective TGF-β-targeting strategies. In this regard, our findings (see Figure 7) suggest that the TGF-β functional switch by 14-3-3ζ and the contextual changes of Smad partners could be utilized as biomarkers to aid in 1) selecting appropriate cancer patients who will benefit from TGF-β antagonists, and 2) determining optimal treatment timing when TGF-β-targeted therapy inhibits cancer.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Yu:
1. Develop more specific, second generation drugs to selectively target the TGF-β signaling in cancer and metastasis without impeding TGF-β’s physiological functions in normal tissues.
2. Use biomarker-guided selection of patients who will most likely respond to second generation selective therapies to effectively target TGF-β signaling in the era of personalized medicine
Citation:
Cancer Cell: Volume 27, Issue 2, 9 February 2015, Pages 177–192
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MedicalResearch.com Interview with:, & Dihua Yu, M.D., Ph.D. (2015). What Makes Growth Factor Switch From Tumor Suppressor to Tumor Promoter? MedicalResearch.com
Last Updated on March 1, 2015 by Marie Benz MD FAAD