Low expression levels of hepsin and TMPRSS3 are associated with poor breast cancer survival

Abstract

Background: Hepsin, (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.

Methods: Immunohistochemical 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.

Results: Low 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.

Conclusions: The 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.

Fig. 1

Immunohistochemical staining of hepsin and TMPRSS3 in invasive ductal breast cancer. Cytoplasmic immunostaining of epithelial tumor cells: a, weak staining of hepsin (score of 1 for intensity); b, intense staining of hepsin (score of 3); c, weak staining of TMPRSS3 (score of 1); d, intense staining of TMPRSS3 (score of 3). All panels, 400x magnification

Fig. 2

Kaplan-Meier survival analysis of the breast cancer patients according to mRNA and protein expression levels. Patients were divided into high and low expression groups relative to the median expression values. Expression of a, TMPRSS1 mRNA (median follow-up time 9.84 years); b, TMPRSS3 mRNA (median follow-up time 9.54 years); c, hepsin protein (median follow-up time 11.05 years); and d, TMPRSS3 protein (median follow-up time 10.94 years)

Fig. 3

Cox regression multivariate analysis of breast cancer survival. Patients were divided into high and low expression groups relative to the median expression values (a, b). Cox regression analysis of survival according to the expression of (a), TMPRSS1 mRNA (median follow-up time 9.79 years); b, TMPRSS3 mRNA (median follow-up time 9.51 years); c, TMPRSS1 and TMPRSS3 mRNA (median follow-up time 9.79 years); and d, hepsin and TMPRSS3 protein expression (median follow-up time 11.05 years). In addition to expression levels, tumor grade, nodal status, tumor size, hormone receptor status, and histologic type were included in the multivariate analyses. Positive nodal status and large tumor size (T3, T4) were other parameters that were significantly associated with poorer breast cancer survival in the multivariate analyses

Fig. 4

Low TMPRSS1 mRNA expression is associated with poor survival in patients treated with radiotherapy in Cox regression multivariate analysis. Cox regression analysis of a, breast cancer-specific survival and b, overall survival according to the TMPRSS1 mRNA expression in patients treated with radiotherapy. Adjustments were made for age, stage, grade, histologic type, hormone receptor status, hormonal treatment, and chemotherapy