Abstract 1754: Transforming growth factor beta as potential prognostic biomarker of breast cancer: Evidence of ‘TGF-β switch’

Abstract

Abstract Purpose: Transforming growth factor-beta (TGF-β1, β2, β3) and its receptors, potent inhibitors of normal epithelial cell proliferation also play a dual role from suppressor to promoter during later stages of breast neoplasia and metastases. No clinical studies have reported the levels of circulatory and tumor tissue TGF-β/TβR/SMAD markers to correlate TGF-β pathway in breast cancer progression. Multifactorial analysis is likely to offer a better predictability and identify patients likely to benefit from anti TGF-β strategies. Experimental Design: This prospective study was designed to evaluate prognostic value of TGF-β, TβR and SMAD in 120 randomly enrolled pre-therapeutic breast cancer patients from Gujarat Cancer & Research Institute, India. Circulating TGF-β levels (β1, β2, β3) were evaluated from patients with known clinicopathologic prognosticators compared to 87 healthy individuals. Gene expression of TGF-β (1, 2, 3), their cognate receptors (TβR-I, II, III) and signaling mediators SMAD (3, 4, 7) from breast tumors and non-involved tissue were determined by Real Time PCR. Kaplan-Meier Survival analysis with a median follow-up of 49 months was performed. Comparisons were made between early and advanced breast cancer to correlate with ‘TGF-β switch’. Results: Circulatory TGF-β1 was higher in advanced stage patients than early stage. Higher levels of TGF-β1 correspond with patients in category of >40-≤60 age, premenopausal, grade-I tumors, ductal carcinomas, moderate + poor differentiated tumors, lymphatic permeation, lymphocytic infiltration, absence of vascular permeation, necrosis and stromal involvement. Reduced overall survival was associated with high TGF-β1. TGF-β1 expression was higher in advanced (31.6%) than early stages (16.7%). TGF-β2 mRNA was higher in 47.6% early and 39.5% advanced stage. Serum TGF-β3 was higher in patients than control. TGF-β3 was downregulated in 97.6% early and 92.1% advanced tumors. TβR-I downregulation of early 85.71%, decreased to 76.32% in advanced stage. TβR-I upregulation correlated reduction in overall survival. TβR-II was downregulated in early tumors and 6.58% advanced tumors showed upregulation. Advanced tumor patients with lower TβR-II relapsed faster than early stage. Notably, TβR-III was downregulated in 30.95% early tumors while 69.05% exhibited an upregulation. TβR-III upregulation was associated with reduced RFS in advanced than early stage patients. All SMAD were downregulated in 88% patients. ERα was upregulated in 44.5% and ERβ downregulated in 97.3% patients. TGF-β2 showed 1.49 fold upregulation in ER negative tumors. Conclusions: The present comprehensive study is the first clinical report of Indian breast cancer patients, indicating the dual role of TGF-β and suggests its potential as a prognostic marker for breast cancer. [Support: ICMR, GCS to ST, Fulbright-Nehru India DPR Fellowship #15094403 to HD] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1754.