Associations of the Transforming Growth Factor β/Smad Pathway, Body Mass Index, and Physical Activity With Breast Cancer Outcomes: Results From the Shanghai Breast Cancer Study

The transforming growth factor beta (TGF-beta) pathway plays an important role in breast cancer progression and in metabolic regulation and energy homeostasis. The prognostic significance of TGF-beta interaction with obesity and physical activity in breast cancer patients remains unclear. We evaluated the expression of TGF-beta type II receptor and pSmad2 immunohistochemically in breast cancer tissue from 1,045 patients in the Shanghai Breast Cancer Study (2002-2005). We found that the presence of nuclear pSmad2 in breast cancer cells was inversely associated with overall and disease-free survival, predominantly among participants with lower body mass index (BMI; weight (kg)/height (m)(2)) and a moderate level of physical activity. However, the test for multiplicative interaction produced a significant result only for BMI (for disease-free survival and overall survival, adjusted hazard ratios were 1.79 and 2.05, respectively). In 535 earlier-stage (T1-2, N0) invasive cancers, nuclear pSmad2 was associated with improved survival among persons with higher BMI (overall survival: adjusted hazard ratio = 0.27, 95% confidence interval: 0.09, 0.86). The cytoplasmic pattern of TGF-beta type II receptor expression in cancer cells was significantly associated with a lower survival rate but was not modified by BMI or physical activity. Our study suggests that the TGF-beta pathway in tumor cells is involved in breast cancer prognosis and may be modified by BMI through pSmad2.