Disrupted Signaling Pathway Turns Tumor Suppressor into Cancer Promoter

Transforming growth factor beta-1 (TGF-beta-1) is an important regulatory protein in normal cells, but disrupted molecular signaling pathways caused by mutations can convert TGF-beta-1 into an active cancer-promoting agent.

In normal cells, TGF-beta, acting through its signaling pathway, halts the cell cycle at the G1 stage to stop proliferation, induce differentiation, or promote apoptosis. When a cell is transformed into a cancer cell, parts of the TGF-beta signaling pathway are mutated, and TGF-beta no longer controls the cell. These cancer cells, as well as surrounding stromal cells (fibroblasts), proliferate. Both types of cells increase their production of TGF-beta. This TGF-beta acts on the surrounding stromal cells, immune cells, endothelial and smooth muscle cells to cause immunosuppression and angiogenesis, which makes the cancer more invasive. TGF-beta also converts effector T-cells, which normally attack cancer with an inflammatory reaction, into regulatory (suppressor) T-cells, which turn off the inflammatory reaction.

Investigators at the University of Texas Southwestern Medical Center (Dallas, USA) mapped the molecular relationships of TGF-beta-1 in normal and human breast cancer cells.

They reported in the December 1, 2009, online edition of The Journal of Clinical Investigation that TGF-beta-1 was critically linked to an enzyme, the ubiquitin ligase human murine double minute (HDM2), which is overexpressed in 40%–80% of late-stage metastatic cancers. Increased HDM2 protein expression caused destabilization of the p53 tumor suppressor protein in human cancer cell lines. Furthermore, histological analyses of human breast cancer samples demonstrated that approximately 65% of late-stage carcinomas were positive for activated HDM2, indicating a strong correlation between TGF-beta-1– mediated induction of HDM2 and late-stage tumor progression.

"These genetic changes would start prior to metastases, so if we detect them early, we might be able to tailor treatment in anticipation of a more aggressive cancer,” said contributing author Dr. David Boothman, professor of radiation oncology, and pharmacology at the University of Texas Southwestern Medical Center.

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University of Texas Southwestern Medical Center