MMP-1 expression has an independent prognostic value in breast cancer

Abstract

Background: Breast cancer consists of a variety of tumours, which differ by their morphological features, molecular characteristics and outcome. Well-known prognostic factors, e.g. tumour grade and size, Ki-67, hormone receptor status, HER2 expression, lymph node status and patient age have been traditionally related to prognosis. Although the conventional prognostic markers are reliable in general, better markers to predict the outcome of an individual tumour are needed. Matrix metalloproteinase-1 (MMP-1) expression has been reported to inversely correlate with survival in advanced cancers. In breast cancer MMP-1 is often upregulated, especially in basal-type breast tumours. The purpose of this retrospective study was to analyse MMP-1 expression in breast cancer cells and in cancer associated stromal cells and to correlate the results with traditional prognostic factors including p53 and bcl-2, as well as to patient survival in breast cancer subtypes.

Methods: Immunohistochemical analysis of MMP-1, ER, PR, Ki-67, HER2, bcl-2, p53 and CK5/6 expression was performed on 125 breast cancers. Statistical analyses were carried out using Kruskal-Wallis and Mann-Whitney -tests. In pairwise comparison Bonferroni-adjustment was applied. Correlations were calculated using Spearman rank-order correlation coefficients. Kaplan-Meier survival analyses were carried out to compare breast cancer-specific survival curves. Factors significantly associated with disease-specific survival in univariate models were included in multivariate stepwise.

Results: Positive correlations were found between tumour grade and MMP-1 expression in tumour cells and in stromal cells. P53 positivity significantly correlated with MMP-1 expression in tumour cells, whereas HER2 expression correlated with MMP-1 both in tumour cells and stromal cells. MMP-1 expression in stromal cells showed a significant association with luminal A and luminal B, HER2 overexpressing and triple-negative breast cancer subtypes.

Conclusions: The most important finding of this study was the independent prognostic value of MMP-1 as well as Ki-67 and bcl-2 expression in tumour cells. Our study showed also that both tumoural and stromal MMP-1 expression is associated with breast tumour progression and poor prognosis. A significant difference of MMP-1 expression by cancer associated stromal cells in luminal A, luminal B and triple-negative breast cancer classes was also demonstrated.

Figure 1

Immunohistochemical staining of MMP-1 in breast cancer. a-b) Immunohistochemical staining of MMP-1 in infiltrating ductal carcinoma GIII. The staining is observed both in nuclei and in the cytoplasm. c) Breast carcinoma cells with positive MMP-1 nuclear staining and with d) positive nuclear and cytoplasm staining and with e) positive tumour cells and cancer associated stromal cells.

Figure 2

Correlation between tumour grade and MMP-1 immunoreactivity. The histograms present an association between the histological grade of the breast cancer and the immunohistochemical expression of MMP-1. P-values for MMP-1 expression in tumour cells: overall p = 0.023, grade I vs. II p = 1.0, grade I vs. III p = 0.81, grade II vs. III p = 0.0177. P-values for MMP-1 expression in stromal cells: overall p = 0.0493, grade I vs. II p = 0.4839, grade I vs. III p = 0.1008, grade II vs. III p = 0.2637.

Figure 3

MMP-1 immunoreactivity of stromal cells of various breast cancer subtypes. Immunohistochemically detected expression of MMP-1 in stromal cells with significant differences in breast cancer subtypes. P-values for overall difference p = 0.0129, luminal A vs. luminal B p = 0.0258, luminal A vs. Her2 p = 0.8334, luminal A vs. triple-negative p = 1.00, luminal B vs. Her2 p = 0.3792, luminal B vs. triple-negative p = 0.0336.

Figure 4

Influence of MMP-1 expression in tumour cells and in stromal cells on survival among women with breast cancer.