TGF-beta switches from tumor suppressor to prometastatic factor in a model of breast cancer progression.
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 II 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.
Tang
Binwu
B
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland, USA.
Vu
Mary
M
Booker
Timberly
T
Santner
Steven J
SJ
Miller
Fred R
FR
Anver
Miriam R
MR
Wakefield
Lalage M
LM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta