Abstract
BackgroundHepsin, (also called TMPRSS1) and TMPRSS3 are type II transmembrane serine proteases (TTSPs) that are involved in cancer progression. TTSPs can remodel extracellular matrix (ECM) and, when dysregulated, promote tumor progression and metastasis by inducing defects in basement membrane and ECM molecules. This study investigated whether the gene and protein expression levels of these TTSPs were associated with breast cancer characteristics or survival.MethodsImmunohistochemical staining was used to evaluate hepsin levels in 372 breast cancer samples and TMPRSS3 levels in 373 samples. TMPRSS1 mRNA expression was determined in 125 invasive and 16 benign breast tumor samples, and TMPRSS3 mRNA expression was determined in 167 invasive and 23 benign breast tumor samples. The gene and protein expression levels were analyzed for associations with breast cancer-specific survival and clinicopathological parameters.ResultsLow TMPRSS1 and TMPRSS3 mRNA expression levels were independent prognostic factors for poor breast cancer survival during the 20-year follow-up (TMPRSS1, P = 0.023; HR, 2.065; 95 % CI, 1.106–3.856; TMPRSS3, P = 0.013; HR, 2.106; 95 % CI, 1.167–3.800). Low expression of the two genes at the mRNA and protein levels associated with poorer survival compared to high levels (log rank P-values 0.015–0.042). Low TMPRSS1 mRNA expression was also an independent marker of poor breast cancer prognosis in patients treated with radiotherapy (P = 0.034; HR, 2.344; 95 % CI, 1.065–5.160). Grade III tumors, large tumor size, and metastasis were associated with low mRNA and protein expression levels.ConclusionsThe results suggest that the TTSPs hepsin and TMPRSS3 may have similar biological functions in the molecular pathology of breast cancer. Low mRNA and protein expression levels of the studied TTSPs were prognostic markers of poor survival in breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1440-5) contains supplementary material, which is available to authorized users.
Highlights
Hepsin, and TMPRSS3 are type II transmembrane serine proteases (TTSPs) that are involved in cancer progression
Low mRNA expression and low protein expression are associated with advanced breast cancer tumor malignancy The results of quantitative real-time PCR and immunohistochemical staining were analyzed for associations with the clinicopathological parameters of each patient
Logistic regression analysis showed that low hepsin and TMPRSS3 protein expression levels were positively associated with advanced clinical stages III and IV and that low hepsin expression was positively associated with larger tumor sizes (T3 and T4; P = 0.034; Odds ratio (OR), 2.266; 95 % Confidence interval (CI), 1.065-4.82), which indicates more extensive disease
Summary
Hepsin, ( called TMPRSS1) and TMPRSS3 are type II transmembrane serine proteases (TTSPs) that are involved in cancer progression. TTSPs can remodel extracellular matrix (ECM) and, when dysregulated, promote tumor progression and metastasis by inducing defects in basement membrane and ECM molecules. A recent study used immunohistochemistry to show that hepsin protein levels were upregulated in human breast cancer tumor samples [14]. Hepsin plays a physiological role as it directly and cleaves laminin-332 (ln-332, previously termed laminin-5), an important ECM protein involved in maintaining the structural integrity of the basement membrane [24]. It was shown recently that hepsin becomes mislocalized when liver kinase B1 (lkb1) expression is lost and that overexpressed hepsin induces basement membrane degradation in breast cancer [25]
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