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TGF-beta switches from tumor suppressor to prometastatic factor in a model of breast cancer progression

  1. Author:
    Tang, B. W.
    Vu, M.
    Booker, T.
    Santner, S. J.
    Miller, F. R.
    Anver, M. R.
    Wakefield, L. M.

  2. Author Address

    NCI, Lab Cell Regulat & Carcinogenesis, Bldg 41,Room C629,41 Lib Dr,MSC 5055, Bethesda, MD 20892 USA NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA Wayne State Univ, Barbara Ann Karmanos Canc Inst, Sch Med, Detroit, MI USA Sci Applicat Int Corp, Pathol Histotechnol Lab, NCI, Frederick, MD USA Wakefield LM NCI, Lab Cell Regulat & Carcinogenesis, Bldg 41,Room C629,41 Lib Dr,MSC 5055, Bethesda, MD 20892 USA
    1. Year: 2003
  2. Journal: Journal of Clinical Investigation
    1. 112
    2. 7
    3. Pages: 1116-1124
  4. Type of Article: Article
  1. Abstract:

    The TGF-beta signaling network plays a complex role in carcinogenesis because it has the potential to act as either a tumor suppressor or a pro-oncogenic pathway. Currently, it is not known whether TGF-beta can switch from tumor suppressor to pro-oncogenic factor during the course of carcinogenic progression in a single cell lineage with a defined initiating oncogenic event or whether the specific nature of the response is determined by cell type and molecular etiology. To address this question, we have introduced a dominant negative type 11 TGF-beta receptor into a series of genetically related human breast-derived cell lines representing different stages in the progression process. We show that decreased TGF-beta responsiveness alone cannot initiate tumorigenesis but that it can cooperate with an initiating oncogenic lesion to make a premalignant breast cell tumorigenic and a low-grade tumorigenic cell. line histologically and proliferatively more aggressive. In a high-grade tumorigenic cell line, however, reduced TGF-beta responsiveness has no effect on primary tumorigenesis but significantly decreases metastasis. Our results demonstrate a causal role for loss of TGF-beta responsiveness in promoting breast cancer progression up to the stage of advanced, histologically aggressive, but nonmetastatic disease and suggest that at that point TGF-beta switches from tumor suppressor to prometastatic factor.

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