Hypoxia-Inducible Factor 1α Regulates the Transforming Growth Factor β1/SMAD Family Member 3 Pathway to Promote Breast Cancer Progression

Purpose: The transforming growth factor β1 (TGF-β1)/SMAD family member 3 (SMAD3) pathway, and hypoxia-inducible factor 1α (HIF-1α) are two key players in various types of malignancies including breast cancer. The TGF-β1/SMAD3 pathway can interact with HIF-1α in some diseases; however, their interaction in breast cancer is still unknown. Therefore, our study aimed to investigate the interactions between the TGF-β1/SMAD3 pathway and HIF-1α in breast cancer.

Methods: Expression of HIF-1α in serum of breast cancer patients and healthy controls was detected by quantitative reverse transcription polymerase chain reaction, and the diagnostic value of HIF-1α for breast cancer was evaluated by receiver operating characteristic curve analysis. Breast cancer cell lines overexpressing SMAD3 and HIF-1α were established. Cell apoptosis and proliferation following different treatments were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and cell counting kit-8, respectively. Expression of related proteins was detected by western blot.

Results: Serum levels of HIF-1α were higher in breast cancer patients than in normal controls. Both SMAD3 and HIF-1α overexpression inhibited cell apoptosis and promoted cell proliferation. Treatment with inhibitors of HIF-1α and SMAD3 promoted apoptosis in breast cancer cells and inhibited their proliferation. Overexpression of HIF-1α promoted the expression of TGF-β1 and SMAD3, while SMAD3 overexpression did not significantly affect expression of HIF-1α or TGF-β1.

Conclusion: HIF-1α serves as an upstream regulator of the TGF-β1/SMAD3 pathway and promotes the growth of breast cancer.