Annals of Oncology Advance Access published online on May 23, 2008
Annals of Oncology, doi:10.1093/annonc/mdn180
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Matrix metalloproteinase expression and outcome in patients with breast cancer: analysis of a published database
1 Department of Pathology and Laboratory Medicine, St Vincent's University Hospital, Dublin 4
2 UCD School of Medicine and Medical Science, Conway Institute, University College Dublin, Dublin 4, Ireland
* Correspondence to: Prof M. J. Duffy, Phd, FRCP Nuclear Medicine Laboratory, St Vincent's University Hospital, Dublin 4, Ireland. Tel: +353-1-2094378; Fax: +353-1-2696018; E-mail: michael.j.duffy{at}ucd.ie
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Abstract |
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Traditionally, matrix metalloproteinases (MMPs) have been implicated in cancer invasion and metastasis. Because of their role in these processes, several MMPs have been investigated for potential prognostic value as well as targets for antimetastatic therapy. In this investigation, we used a publically available database to relate messenger RNA expression levels for 17 different MMPs to tumor characteristics and outcome in patients with breast cancer. Of the MMPs investigated, only MMP-1 was significantly increased in tumors >2 cm in size compared with those
2 cm while MMP-1, -9, -12 and -15 were significantly elevated in high-grade compared with low-grade tumors. Only MMP-10 was higher in lymph node-positive compared with lymph node-negative cancers. Using univariate analysis, high expressions of MMP-1, -9, -12, -14 and -15 were associated with poor overall survival. Of these five, only MMP-14 predicted outcome independent of tumor size, tumor grade and lymph node status. None of the MMPs investigated were associated with good outcome. We conclude that only a minority of MMPs, i.e. MMP-1, -9, -12, -14 and -15, are associated with adverse outcome in patients with breast cancer. These MMPs are likely to be involved in mediating breast cancer progression and may thus be good targets for designing specific MMP inhibitors for the treatment of breast cancer. breast cancer and prognosis, metalloproteinases
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introduction |
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The matrix metalloproteinases (MMPs) in humans are a family of 23 members that have classically been associated with remodeling of the extracellular matrix (ECM) (for review, see refs. [1, 2]). Because of their involvement in processing of the ECM, MMPs were implicated in cancer invasion and metastasis [3, 4]. Consistent with this hypothesis, multiple data from model systems suggested that specific MMPs were causally involved in metastasis [3, 4].
The involvement of MMPs in cancer dissemination led to the development of MMP inhibitors (MMPIs) for the treatment of malignancy [5–7]. Although these inhibitors reduced or blocked the formation of metastasis in animal models, results from clinical trials were disappointing due to poor efficacy and toxic side-effects [5–7]. Indeed, in some studies, there were suggestions that the MMPIs may have promoted cancer progression [7].
These disappointing findings lead to a reconsideration of the role of MMPs in cancer and prompted detailed studies on specific MMPs in preclinical cancer models. Somewhat surprisingly, this research suggested that certain MMPs (e.g. MMP-3 and -8), rather than promoting cancer, were inhibitory against cancer, at least in some situations [8–10]. Thus, the current thinking, on the basis of animal models, is that while some MMPs promote cancer formation/progression, others inhibit this process [8–10].
If MMPIs are to be used in the treatment of cancer, it is important to know which members promote and which protect against malignancy. In an attempt to address this question, we used a published database to carry out a detailed investigation into 17 MMPs in breast cancer. Consistent with a role in cancer formation/progression, we found that high expressions of five MMPs (i.e. MMP-1, -9, -12, -14 and -15) predicted poor outcome. None of the MMPs investigated, including those implicated in protection against cancer/cancer progression, were associated with good outcome.
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materials and methods |
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The tumors analyzed were from a previously published database of 295 consecutive women diagnosed with breast cancer [11]. Detailed data relating to the patient and tumor characteristics are available from Rosetta Inpharmatics Inc., Kirkland, Washington, DC, USA (http://www.rii.com). These data are summarized in Table 1. All patients were treated with modified radical mastectomy or breast-conserving surgery, followed by radiotherapy if indicated. Adjuvant systemic therapy was given to 10 of 151 patients with lymph node-negative disease and 120 of 144 that had node-positive disease (90 patients received chemotherapy, 20 hormone therapy, while 20 were given combined chemotherapy and hormone therapy). The median follow-up for all patients was 6.7 years (range 0.05–18.3 years). Significantly, there were no missing data [11].
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Raw data were extracted from the dataset using accession numbers from National Center for Biotechnology Information (http://www.ncbi/nlm.nih.gov/). Nonparametric analyses were carried out as MMP concentrations were not normally distributed. The Mann–Whitney U test was used for relating MMP levels to the clinicopathological variables (hormone receptor status, tumor grade, tumor size, nodal status). For patient outcome analysis, all the MMPs were treated as continuous variables, using log ratio values. This has the advantage of retaining all the information and avoiding arbitrary cut-off points. Both univariate and multivariate analyses of events were carried out using Cox proportional hazards model. Relative risk values with 95% confidence intervals (CIs) were used to describe the observed results. All P values were two sided. MMPs that were statistically significant at the 0.01 level in univariate analysis were included in the multivariate proportional hazards model. This low P value was selected because of the large number of variables investigated. Stepwise and backwards regression was used in order to obtain the final model. All statistics were carried out using SPSS version 11.0 (SPSS Inc., Chicago, IL).
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relationship between MMP mRNA expression and tumor characteristics
mRNA levels for 17 MMPs were related to estrogen receptor (ER) status, tumor size, tumor grade and lymph node status (Table 2). Several MMPs such as MMP-1, -7, -9, -10, -12 and -15 were significantly increased in ER-negative compared with ER-positive cancer. Levels of only MMP-1 were significantly increased in tumors with size >2 cm vis-a-vis those
2 cm. MMP-1 as well as MMP-9, -12 and -15 were higher in grade 3 compared with grade 1 and 2 tumors. Only expression of MMP-10 was increased in lymph node-positive compared with lymph node-negative cancers.
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relationship between MMP mRNA expression and molecular subtype of tumor
Gene expression studies using microarray have identified five new molecular subtypes of breast cancer, i.e. luminal A, luminal B, human epidermal growth factor receptor-2 (HER-2), normal beast like and basal like [12, 13]. The basal type is comprised almost entirely of tumors lacking ER, PR and HER-2, i.e. are triple receptor negative. Unlike the other subtypes, targeted therapy does not exist for the basal type. We therefore compared expressions of the different MMPs in basal and nonbasal tumors in an attempt to identify potential new targets for treatment of the basal subtype. Table 3 outlines the treatment regimens received by patients in these subgroups. As shown in Table 4, expressions of MMP-1, -7, -9, -12 and -15 were significantly elevated in the basal type compared with all the other subtypes combined.
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relationships between mRNA expression of the different MMPs
The expression level of each MMP analyzed was related to that of all the others (Table 5). As can be seen, multiple statistically significant but weak correlations were found between many of the MMPs. The strongest relationships were between MMP-2 and -11, -13 and -14 as well as between MMP-13 and -14.
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relationship between MMP mRNA expression and overall survival
Each MMP, treated as a continuous variable, was related to patient outcome (Table 6). Using univariate analysis, increasing expressions of MMP-1, -9, -12, -14 and -15 were significantly associated with poor overall survival (OS). Each of the MMPs found to be significant in the univariate analysis were then included in multivariate model that included tumor size, tumor grade, lymph node status and ER status. Following multivariate analysis, only MMP-14 was significantly associated with patient outcome (Table 7).
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Approximately half of the 295 patients in the database analyzed received some form of adjuvant systemic therapy. For these patients, it was not possible to establish whether the variables investigated were prognostic or predictive of therapy response. In order to establish whether any of the MMPs were pure prognostic factors, each was related to outcome in the cohort of patients who did not receive systemic adjuvant therapy (Table 6). All the MMPs associated with poor outcome in the total population of patients, apart from MMP-9, were also associated with adverse outcome in those who did not receive systemic adjuvant therapy.
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discussion |
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Several studies have previously investigated the potential prognostic impact of individual MMPs in different cancer (for review, see refs. 14–16). Most of these studies were retrospective and contained small numbers of poorly defined patient populations. In the different studies, a variety of cut-off points were used to differentiate patients with poor and good outcome. Few, if any of the findings, have been validated in external patient populations. Furthermore, in many of these studies, it was unclear how many patients received systemic adjuvant therapy, making it difficult to differentiate a potential prognostic from a potential predictive impact. Consequently, findings have been conflicting [14–16], with no clearly defined prognostic impact for any MMP in any cancer, at this point in time.
Our analysis of a published database is the most comprehensive study to date on MMPs in a human cancer. The cohort of patients used for the analysis was defined with respect to detailed tumor characteristics as well as adjuvant systemic therapy administered to the patients. Most important, the process by which patients were selected was described, i.e. they were a consecutive series of 295 new patients presenting with a diagnosis of breast cancer. Furthermore, in an attempt to investigate a potential pure prognostic impact for the different MMPs, analysis was also carried out on the subgroup of patients who were not given systemic adjuvant therapy.
Of the 17 MMPs investigated, only five, i.e. MMP-1, -9, -12, -14 and -15, were significantly associated with poor outcome. All these MMPs, apart from MMP-9, were also associated with outcome in the systemically untreated patients, suggesting that these are pure prognostic factors for breast cancer. Of the 5 MMPs associated with outcome in univariate analysis, only MMP-14 was an independent predictor of outcome, i.e., independent of tumor size, tumor grade, lymph node status and ER status.
Most of the MMPs associated with adverse outcome in this study had previously been investigated in preliminary studies for potential prognostic value in breast cancer. Cheng et al. [17], in a study on 85 patients with a median follow-up of 38 months, reported that elevated levels of MMP-1 mRNA were a risk factor for poor outcome in patients with breast cancer. In a further study, MMP-1 was identified as a potential marker for identification of non-malignant breast lesions likely to progress to invasive breast cancer [18]. In a preclinical model of breast cancer, MMP-1 was found to promote metastasis to both bone and lung [19, 20]. Indeed, MMP-1 was one of only four genes implicated in the multiple steps in the dissemination of breast cancer to lung, i.e., it not only promoted the growth of primary tumors but also entry of disseminating cells into the vasculature, their colonization of the lung, extravasation and growth at metastatic site [21]. All these findings, when taken together, are consistent with a role for MMP-1 in breast cancer progression.
A novel result in the current study was the up-regulation of MMP-1 expression in basal-type cancers compared with nonbasal types. As mentioned above, targeted therapies exist for the nonbasal subtypes of breast cancer, for example hormone therapy is almost universally administered to luminal A and B subtypes which express ER while trastuzumab (Herceptin) may be administered to patients with the HER-2 type. Currently, the only systemic therapy available for patients with the basal type is chemotherapy. There is thus, at present, considerable interest in identifying new targets for the treatment of the basal subtype of breast cancer. Our findings suggest that MMP-1 might be such a target.
A number of studies have related MMP-9 to outcome in patients with breast cancer. Using immunohistochemistry in lymph node-negative patients, Li et al. [22] reported that increased expression of MMP-9 was significantly associated with relapse-free survival but not with OS. Rahko et al. [23] found that MMP-9, as determined by immunohistochemistry, failed to predict outcome in the total population investigated but was associated with adverse outcome in the ER-negative subgroup of patients. In contrast to these findings, Scorilas et al. [24] reported that elevated expression of MMP-9 protein was predictive of a good outcome in 84 lymph node-negative patients. In yet another study, MMP-9 in stromal cells correlated with poor outcome in the ER-positive subgroup of patients while its expression in cancer cells was associated with good outcome [25]. It is of interest that in our analysis, MMP-9 was prognostic in the total population of patients but was not significantly associated with outcome in the systemically untreated cohort. This finding suggests that the predictive impact of MMP-9 may depend on whether or not patients received adjuvant systemic therapy. In animal models, although most studies suggested that MMP-9 promoted metastasis, a few found that this MMP was protective against malignancy [8–10].
In contrast to MMP-9, relatively little work has been carried out on MMP-12 (metalloelastase) in cancer, especially in breast cancer. Elevated expression of MMP-12 however, predicted good outcome in patients with colorectal cancer [26] and poor outcome in patients with non-small-cell lung cancer [27]. In squamous cancer of the vulva, MMP-12 in malignant cells appeared to be protective while its expression in macrophages suggested a promotional role [28]. In lung cancer models, MMP-12 was reported to be protective against cancer [29, 30]. Our finding here appears to be the first to show that high expression of MMP-12 in breast cancer is associated with adverse outcome.
As with MMP-12, relatively little work has been carried out on the role of MMP-14 in cancer. Using a mouse model system, this MMP was shown to be responsible for both track widening and transition from individual to multicellular invasion [31]. Consistent with this finding Têtu et al. [32], using in situ hybridization, reported that elevated MMP-14 mRNA expression was an independent predictor of adverse outcome in patients with breast cancer. Our findings of an independent prognostic impact of MMP-14 is thus in agreement with those of Têtu et al. [32]. Indeed, of all the MMPs investigated by us, MMP-14 was the only one that was an independent predictor of outcome.
MMP-15 is one of the least-studied MMPs in cancer. In cervical cells in culture, this MMP, however, was found to inhibit apoptosis [33]. The relevance of this in vitro finding to cancer formation/progression is unclear. Our result showing that elevated expression of MMP-15 is associated with poor outcome in breast cancer appears to be one of the first to demonstrate a prognostic impact for this MMP in any cancer. In contrast to MMP-14, however, MMP-15 was not an independent prognostic factor.
Some MMPs that had previously been reported to predict patient outcome in breast cancer were not associated with OS in the present study. This applies especially to MMP-2 [15] and -11 (stromelysin 3) [34]. Indeed, MMP-11 is one the 16 cancer-associated genes used in the Oncotype DX test for predicting recurrence in breast cancer, following treatment with adjuvant tamoxifen [35]. A possible reason why MMP-2 failed to be prognostic in the present study may be our use of mRNA as opposed to protein in the published studies [15]. Why MMP-11 lacked prognostic impact in the current analysis in contrast to a previous studies [34, 35] is unclear.
Our results, showing that MMP-1, -9, -12, -14 and -15 are associated with poor outcome in patients with breast cancer, are consistent with a role for these proteinases in breast cancer progression. These specific MMPs are thus putative targets for new treatments for breast cancer. None of the MMPs analyzed in this study were associated with favorable patient outcome. This finding might appear to be inconsistent with a protective role for specific MMPs in human cancer as has been found in some preclinical models [8–10]. However, they do not rule out such a role in human cancer. Indeed, some of the MMPs investigated here may have been protective during an early phase of breast carcinogenesis. Such a protective effect could be lost following formation of an invasive malignancy.
A limitation of the current study is that MMP expression was analyzed at mRNA rather than at protein level. Of course, it is the latter that mediates biological actions and are the primary targets for MMPIs. A second limitation was that MMP mRNA expression levels were derived from tumor cell-free extracts that would have contained both the stromal and epithelial transcriptomes. Immunohistochemical and in situ hybridization analyses show that with few exceptions (e.g. MMP-7), most of the MMP expression in tumors is located in stromal rather than epithelial cells (for review, see refs. 5, 8). Consequently, if MMP expression in these different cell types were separately measured, different findings might have emerged, i.e. expression in the different cell types might have different impacts on patient outcome. Indeed, it was mentioned above that high MMP-9 protein in stromal cells in breast cancer was associated with poor outcome whereas high expression in tumor cells predicted good outcome [25].
In conclusion, our analysis of a published database containing well-characterized tumors and patients show that MMP-1, -12, -14 and -15 are predictors of poor outcome in patients with breast cancer, including patients who did not receive systemic therapy. These four MMPs are thus pure prognostic factors for breast cancer. Of the four MMPs, however, only MMP-14 was an independent predictor of outcome. Before these MMPs can progress to clinical use in determining prognosis, our findings will require validation in a prospective trial. Our results when combined with previously published preclinical data suggest that MMP-1, -12, -14 and -15 are involved in breast tumor progression. These MMPs may therefore be targets for designing specific MMPIs for the treatment of breast cancer. Finally, since MMP-1, -12 and -15 were preferentially elevated in basal-type tumors, these three MMPs may be targets for the treatment of this subtype of breast cancer.
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Health Research Board of Ireland (Breast Cancer Metastasis: Biomarkers and Functional Mediators, PRP/2005/35).
Received for publication January 17, 2008. Revision received March 28, 2008. Accepted for publication March 31, 2008.
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