A dual prognostic role for the TGFß receptors in human breast cancer.

The transforming growth factor-ß (TGFß) plays a dual role in breast cancer, acting as a tumor suppressor in early carcinomas while promoting tumor metastasis in more advanced breast carcinoma. As a result, the prognostic role of TGFß and its signaling components in breast cancer remains unclear. Here we evaluated the expression levels of TGFß signaling receptors TßRII and TßRI using human breast cancer tissue microarrays and a large publicly available gene profiling database in relation to various clinicopathological parameters. Our results indicate that breast cancer tissues express lower TßRII and TßRI protein levels compared with normal breast tissue. In contrast to TßRI expression, TßRII mRNA expression levels were also significantly downregulated in invasive breast cancer compared with normal breast tissue (4.18-fold downregulation, P=9.3×10-115). Interestingly, within the cancer cases analyzed, our results revealed a direct correlation between high TßRII and TßRI expression levels and classic poor prognostic clinicopathological parameters, including larger tumor size, advanced tumor stage, and poorly differentiated tumors. Next, we examined TGFß receptors' expression in relation to breast cancer molecular subtypes. Importantly, our results revealed that whereas expression of TGFß receptors in luminal A and triple-negative breast cancer showed no correlation with patient outcome, their expression in luminal B and HER2 subtypes showed significant association with favorable patient outcome. Together, these results indicate that although TGFß receptors are downregulated in breast cancer, their expression in tumors is an indicator of aggressive breast cancer phenotype. Moreover, the relation between TGFß pathway and patient outcome is breast cancer subtype dependent.