Smad4-expression is decreased in breast cancer tissues: a retrospective study

Abstract

BackgroundAlthough transforming growth factor β (TGF-β) typically inhibits proliferation of epithelial cells, consistent with a tumor suppressor activity, it paradoxically also exhibits pro-metastatic activity in the later stages of carcinogenesis. Since tumors often display altered TGF-β signaling, particularly involving the Smad-pathway, we investigated the role of Smad4-expression in breast cancer.MethodsSmad4 expression was investigated by immunohistochemistry in formalin-fixed, paraffin-embedded tissue from 197 samples of primary breast cancer obtained between 1986 and 1998. The prognostic value of Smad4-expression was analyzed.ResultsSmad4 expression was found to be reduced in lobular and ductal breast carcinoma as compared to surrounding uninvolved lobular and ductal breast epithelia (p < 0.001, n = 50). Smad4-expression correlated positively with expression of TGF-β-receptor I (p < 0.001, n = 197) and TGF-β-receptor II (p < 0.001, n = 197), but showed no significant correlation with tumor size, metastases, nodal status, histological grade, histological type, or estrogen receptor expression. While not achieving statistical significance, there was a trend towards longer survival times in patients with Smad4 negative tumors.ConclusionAccording to the suggested role of Smad4 as a tumor suppressor we observed that expression of Smad4 is lower in human breast cancer than in surrounding breast epithelium. However, we also observed a trend towards longer survival times in Smad4-negative patients, indicating the complex role of TGF-β signaling in tumor progression.

SMAD4 expression in breast ductal carcinoma correlates with prognosis

“…Notably, it was also demonstrated that among the 86 patients undergoing surgical resection of breast ductal carcinoma, the loss of SMAD4 expression was independently associated with poor prognosis. Patients with SMAD4-negative cancers exhibited a 2-fold greater risk of The present observation of decreased SMAD4 protein expression in breast ductal carcinoma was in agreement with the reports of Stuelten et al (37) and Ren et al (25), which also demonstrated that SMAD4 protein expression was markedly downregulated or lost in breast ductal carcinoma when compared with that in the normal breast epithelium. However, Ren et al (25) further observed that SMAD4 was highly expressed in the cytoplasm and nucleus of benign breast ductal epithelial cells, whereas it was only weakly expressed and largely restricted to the cytoplasm of cancer cells.…”

“…Despite one report, which demonstrated that loss of SMAD4 expression resulted in a trend for increased survival times in a subgroup of 197 cases of breast ductal carcinoma (N1 or ER-negative, respectively) (37), in the present series of 86 patients it was demonstrated that loss of SMAD4 expression was associated with increased risk of recurrence and shorter survival time. This finding corroborates the results of a study by Stuelten et al (37), which indicated that the survival curve of SMAD4-negative patients was marginally better than that of SMAD4-positive patients in terms of overall 5-year survival, although this difference was not statistically significant. These contradictory results may be due to the differences in sampling and clinical management of the disease.…”

“…The present data indicated that SMAD4 protein levels were significantly decreased from grade I to III, suggesting that SMAD4 inactivation is associated with the advanced disease state of breast cancer. Analogously, western blot analysis of breast cancer cells with increasing malignancy revealed that SMAD4 protein expression decreased concurrently with increasing malignancy of the tumor cell line, suggesting that decreased SMAD4 protein expression may accompany tumor progression from the early stages of cancer, as demonstrated in situ and in vivo (37). As the key intracellular mediator of transcriptional responses to TGF-β signaling, which is altered in various tumors (42), SMAD4 consistently transmits the TGF-β signal from the cell membrane to the nucleus.…”

Early Diagnosis with 11-Gene Panel Screening for Non Small Cell Lung Cancer

“…Molecular detection in lung cancer also was used as predictor, such as TGF-β1, which may be an independent predictor of survival in resected lung adenocarcinoma patients [27]. SMAD4 was identified as a tumor suppressor gene and was associated with tumor invasion, metastasis and prognosis in different cancers including NSCLC [28,29]. C-Kit have critical roles in cell proliferation and differentiation in patients with NSCLC which indicate that C-Kit is a strong, independent prognostic factor in NSCLC [30].…”

Synergistic repression of estrogen receptor transcriptional activity by FHL2 and Smad4 in breast cancer cells

“…The tumor suppressor Smad4 acts as a central mediator of transforming growth factor b (TGF-b) signaling that plays important roles in regulating cell proliferation, differentiation, migration, apoptosis, and development (12,13). Alterations in Smad4 gene were identified in many types of cancers, including pancreatic, breast, and ovarian cancers.…”