Expression of Transforming growth factor beta in Breast Cancer Subtypes

Abstract

Background: Normally, transforming growth factor beta (TGF-b) functions as a tumorsuppressor. But, during carcinogenesis, malignant cells become insensitive to TGF-b´s growth inhibitory abilities, and the traits of TGF-b alter. This results in an increased TGF-b production in tumor- and surrounding stromal cells, and leads to further tumor development including epithelial-mesenchymal transition and formation of cancer-associated fibroblasts. Aims: This study aimed to investigate associations between TGF-b expression in stroma and tumor-epithelial cells, molecular subtypes of breast cancer, histopathological type, grade, and breast cancer specific survival (BCSS) in a cohort of Norwegian breast cancer patients. Methods: The study population comprised 759 cases of breast cancer reclassified into molecular subtypes and assembled in tissue microarrays (TMA). Immunohistochemistry (IHC) for TGF-b was carried out, and epithelial intensity and proportion of stained cells, and stromal staining were annotated. Kaplan-Meier and Cox proportional hazard methods were used for survival analyses for estimating risk of death according to theTGF-b profile. Results: In total, 87.5% of the cases were positive for TGF-b in the epithelium, and 84.5% in the stroma. TGF-b expression was not associated with molecular subtype, histopathological type or grade, and there were no statistical significant associations between epithelial or stromal TGF-b expression and BCSS. A correlation between stromal and epithelial TGF-b expression was observed, in addition to a concurrent increase in epithelial proportion and intensity. The tumour tissue showed heterogeneity in staining distribution, and 5.7% demonstrated a gradually increasing epithelial staining intensity towards the stroma at the invasive edge. 4.4% showed an uneven distribution within a single glad structure with increased intensity in epithelial cells bordering intratumoral stroma. Conclusion: No association between TGF-b and molecular subtype, histopathological type, grade or BCSS was found in our study. However, we have demonstrated that TGF-b appears to be expressed in epithelial tumor cells closed to the invasive edge of the tumour, and in epithelial cells bordering on areas of intratumoral stroma. Our TMA based study may underestimate the frequency of this finding, and a study of TGF-b expression in full face sections would be necessary for validation.