Twenty-five to thirty percent of patients with node-negative breast cancer are expected to relapse following surgery, therefore great efforts have been made to identify new prognostic markers that could be useful in defining patients for additional therapy. The expression of MMP-2 and MMP-9 has been associated with high potential of metastasis in several human carcinomas including breast cancer. In the present study we examined the prognostic value of immunoreactive MMP-2/MMP-9 protein in 270 consecutive lymph node negative cases who received radical mastectomy or modified radical mastectomy. Among the patients, 211 cases received adjuvant endocrine therapy and/or adjuvant chemotherapy. Using immunohistochemical assay, we found that 56.7% of the resected tumors were positive for MMP-2 whereas 59.6% of the samples were positive for MMP-9. Chi2 test demonstrated a significant direct association between MMP-2 and MMP-9 (p < 0.001); positive immunostaining of MMP-2 was significantly related to higher tumor grade (p < 0.001) and larger tumor size (p = 0.012); positive immunostaining of MMP-9 was significantly related to higher tumor grade (p = 0.002). In univariate analysis, using Cox-proportional hazard model we found MMP-2, MMP-9 and the co-expression of MMPs (MMP2/MMP9) were significantly associated with patients' relapse free survival (p = 0.016, 0.015 and 0.013 respectively) but not overall survival (p = 0.122, 0.320 and 0.091 respectively). Log-rank test also showed that MMP-2, MMP-9 or the co-expression of MMP2/MMP9 was unfavorable prognostic factor for relapse free survival but not overall survival. In subgroup analysis, we found MMPs were more prognostic for patients with no adjuvant treatment than for patients with adjuvant therapy. In multivariate analysis, using Cox-proportional hazard model we found co-expression of MMPs, larger tumor size and higher tumor grade were unfavorable for relapse free survival (p = 0.038, 0.007 and 0.015 for each). We concluded that MMP-2 and MMP-2 are unfavorable prognostic factors in breast cancer patients. They might be potential predictive factor for adjuvant systemic therapy. The co-expression of MMP-2 and MMP-9 has significantly prognostic value in node-negative patients.

Recent studies of ERs in breast cancer have demonstrated the existence of ERb in addition to ERa. Some clinical data indicated that ERb had prognostic value for patient's survival, which suggested that ERb plays a key role in breast cancer development and metastasis. To test this hypothesis, we generated an ERb high-expression cell line by reintroduced human ERb cDNA into MDA-MB-435 cells. We demonstrated that ERb exerted multiple tumor-stimulative effects on human breast carcinoma cells both in vivo and in vitro. In in vitro studies, ERb was able to increase the proliferation and invasion of MDA-MB-435 cells significantly, while these effects were totally estradiol independent. Also, this stimulation was characterized by downregulation of p21 and upregulation of MMP-9, as well as transcriptional factor Est-1. In in vivo studies, we also demonstrated that ERb-transfected MDA-MB-435 cells grew much faster and had more pulmonary metastasis than mock or wild-type cells in nude mice. In ERb-transfected MDA-MB-435 xenografts, ERb caused significant reduction in p21 protein levels. Similar effects of ERb on MMP-9 and Ets-1 expression noted in vitro studies were also observed in the in vivo studies. These in vitro and in vivo studies indicated that ERb exerted multiple stimulative effects on breast cancer development and metastasis.

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TAM resulted in additional benefit to premenopausal patients with node-positive ER-positive breast cancer who received the CMF polychemotherapy regimen.