Science et thérapie du cancer

Differential Gene Expression Pattern of Transforming Growth Factor Beta-1 in Early and Advanced Breast Cancers

Abstract

Heena V Dave, Manoj J Shah, Shilin N Shukla and Sunil N Trivedi

Background: Transforming Growth Factor Bs (TGF-?s) are pluripotent polypeptides that switch function from growth suppressor to promoter during breast tumorigenesis. This integral function in tumor progression offers it as an attractive target of cancer therapy. Amongst the three mammalian isoforms, TGF-?1 is the most potent, abundant and is considered to be the representative of TGF-? pathway. Higher circulating TGF-?1 is known to affect prognosis, increase relative risk of recurrence and reduced survival in breast cancer. Altered gene expression is determined in breast cancer cell lines; however it is less explored in clinical breast cancer. Methods: We investigated expression of TGF-?1 with an aim to explore its utility as biomarker. TGF-?1 gene expression was determined from breast cancer patients (N=118) using Real-Time PCR. The relative quantitation was determined by ddct method and differences were expressed as mean fold change (MFC) using GAPDH as endogenous control and adjacent normal tissue of each patient as calibrator. TGF-?1 gene expression was correlated with clinicopathologic prognosticators. Relapse-free and overall survival were assessed by Kaplan-Meier Survival analysis with log-rank test. Results: TGF-?1 mRNA was downregulated in early stage tumors (1.46 fold) whereas it was upregulated in advanced stage tumors (1.60 fold; p=0.05). Higher downregulation was seen in perimenopausal- than postmenopausal- patients (p=0.022). Node positive and node negative patients exhibited differences in early and advanced tumors (p=0.00001). Ductal carcinoma showed highest downregulation however, linear correlation was seen with grade+++ stromal involvement. Reduced disease-free survival (DFS) was noted in tumors with downregulation and advanced stage than early stage patients. Conclusion: We conclude that downregulation of TGF-?1 is associated with poor disease-free survival. TGF-?1 may play a significant role in the invasiveness and metastatic potential of breast cancer. The magnitude of downregulation is believed to be responsible for disease progression and can be used as predictive and prognostic marker.