Prognostic Significance of Transforming Growth Factor β Receptor II in Estrogen Receptor-Negative Breast Cancer Patients

Abstract

Purpose: The role of transforming growth factor ␤ (TGF-␤) in breast cancer is ambiguous; it can display both tumor suppressing and enhancing effects. Activation of the TGF-␤ signal transduction system is subject to hormonal regulation. This study was conducted to further analyze the role of TGF-␤ receptors in breast cancer and to evaluate their significance as prognostic markers. Experimental Design: Expression of TGF-␤ receptor I (T␤RI) and TGF␤ receptor II (T␤RII) was retrospectively analyzed by immunohistochemistry in 246 breast cancer patients.Results: Expression of T␤RI was strongly correlated with tumor size (P < 0.001) and nodal status (P ‫؍‬ 0.012) but only weakly with overall survival (P ‫؍‬ 0.056). In contrast, T␤RII was prognostic for overall survival in univariate analysis (P ‫؍‬ 0.0370). In estrogen receptor (ER) -negative patients T␤RII expression was correlated with highly reduced overall survival (P ‫؍‬ 0.0083). In multivariate analysis T␤RII proved to be an independent and highly significant prognostic marker with a hazard ratio of 6.8. Simultaneous loss of both ER and T␤RII was associated with longer overall survival times comparable with those of ER-positive patients.Conclusions: The results of this exploratory study show that T␤RII is an independent, highly significant prognostic indicator for overall survival in ER-negative patients. In addition our results are supportive of a mechanism of breast cancer progression in which a selective loss of the tumor inhibitory action of TGF␤ takes place, whereas tumorpromoting aspects remain intact.

Estrogen receptor α attenuates transforming growth factor-β signaling in breast cancer cells independent from agonistic and antagonistic ligands

“…By KaplanMeier analysis, we identified a correlation between the expression of TGF-b receptor II and a highly reduced overall survival in ER-negative breast cancer patients [14]. These findings indicate a coupling of both groups in a functional network and strongly presume a crosstalk between ERa and components of the TGF-b pathway in breast cancer cells.…”

“…This mechanism also explains the role of TGF-b in ERa-positive and ERa-negative patients according to the overall survival, which we studied in 2004. The expression of TGF-b receptor type II in ERanegative patients is correlated with highly reduced overall survival, whereas simultaneous loss of both ERa and TGF-b receptor type II is comparable with down-regulation of TGF-b signaling and was associated with longer overall survival [14]. Moreover, the inhibitory function of ERa is independent from the ligand-dependent receptor function and a loss of ERa would result in a poor prognosis, which actually was shown in several studies [1,2,40].…”

“…According to our preclinical observations we postulated an interference of ERa with components of the TGF-b signaling pathway [14]. To verify this hypothesis, we carried out knock down experiments using ER-positive breast cancer cells MCF-7.…”

TGFβ1 regulates HGF‐induced cell migration and hepatocyte growth factor receptor MET expression via C‐ets‐1 and miR‐128‐3p in basal‐like breast cancer

“…In line with these findings, we demonstrate that TGFBR2 is expressed at higher levels in more aggressive basal‐like breast cancer cell lines as well as in triple‐negative breast cancer tissue than in luminal breast cancer cell lines and luminal‐like tumor tissue. This subtype‐specific expression of TGFBR2 might explain why TGFBR2 expression correlates with reduced overall survival of patients with ER‐negative but not with ER‐positive breast cancer (Buck et al ., 2004). Nevertheless, the exact mechanisms of TGFβ1/TGFBR2‐driven breast cancer progression and metastasis have not been fully elucidated until now.…”

“…We have previously shown that TGFβ signaling and TGFβ receptor type‐2 (TGFBR2) seem to have a tumor promoting role in human estrogen receptor (ER)‐negative breast cancer (Keklikoglou et al ., 2012). In addition, clinical studies in ER‐negative breast tumors indicated a correlation of elevated TGFBR2 levels with shorter overall breast cancer patient survival (Buck et al ., 2004). However, the molecular mechanisms of TGFβ signaling and elevated TGFBR2 expression are likely diverse and have not been fully elucidated.…”