Plasma MMP1 and MMP8 expression in breast cancer: Protective role of MMP8 against lymph node metastasis

Abstract

BackgroundElevated levels of matrix metalloproteinases have been found to associate with poor prognosis in various carcinomas. This study aimed at evaluating plasma levels of MMP1, MMP8 and MMP13 as diagnostic and prognostic markers of breast cancer.MethodsA total of 208 breast cancer patients, of which 21 with inflammatory breast cancer, and 42 healthy controls were included. Plasma MMP1, MMP8 and MMP13 levels were measured using ELISA and correlated with clinicopathological characteristics.ResultsMedian plasma MMP1 levels were higher in controls than in breast cancer patients (3.45 vs. 2.01 ng/ml), while no difference was found for MMP8 (10.74 vs. 10.49 ng/ml). ROC analysis for MMP1 revealed an AUC of 0.67, sensitivity of 80% and specificity of 24% at a cut-off value of 4.24 ng/ml. Plasma MMP13 expression could not be detected. No correlation was found between MMP1 and MMP8 levels. We found a trend of lower MMP1 levels with increasing tumour size (p = 0.07); and higher MMP8 levels with premenopausal status (p = 0.06) and NPI (p = 0.04). The median plasma MMP1 (p = 0.02) and MMP8 (p = 0.007) levels in the non-inflammatory breast cancer patients were almost twice as high as those found in the inflammatory breast cancer patients. Intriguingly, plasma MMP8 levels were positively associated with lymph node involvement but showed a negative correlation with the risk of distant metastasis. Both controls and lymph node negative patients (pN0) had lower MMP8 levels than patients with moderate lymph node involvement (pN1, pN2) (p = 0.001); and showed a trend for higher MMP8 levels compared to patients with extensive lymph node involvement (pN3) and a strong predisposition to distant metastasis (p = 0.11). Based on the hypothesis that blood and tissue protein levels are in reverse association, these results suggest that MMP8 in the tumour may have a protective effect against lymph node metastasis.ConclusionIn summary, we observed differences in MMP1 and MMP8 plasma levels between healthy controls and breast cancer patients as well as between breast cancer patients. Interestingly, our results suggest that MMP8 may affect the metastatic behaviour of breast cancer cells through protection against lymph node metastasis, underlining the importance of anti-target identification in drug development.

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…Furthermore, MMP-8 provides a protective effect in the metastatic process, decreasing the metastatic potential of breast cancer cells when it is over-expressed (Decock et al, 2008). Similarly, MMP-8 expression in the squamous cell carcinoma of the tongue is correlated with improved survival of patients and it is proposed that this protective action is probably correlated with the role of estrogen in the growth of tongue squamous cell carcinomas (Ardi et al, 2007;Korpi et al, 2008).…”

A functional genetic screen reveals new regulators of β1-integrin activity

“…In line with this, one of the negative regulators of integrin activity, MMP8 has been shown to have a protective role against inflammation in arthritis and lung fibrosis by suppressing the expression or availability of inflammatory players such as IL-1b and IL-10 ( GarciaPrieto et al, 2010). In addition, a reduction of the plasma levels of MMP8 has been associated with higher lymph node and distant metastasis in inflammatory breast cancer patients (Decock et al, 2008). Thus, the mechanistic connection of inflammation and integrin activity regulation in cancer would be an interesting topic for future studies.…”

ANKRD1 Acts as a Transcriptional Repressor of MMP13 via the AP-1 Site

“…MMP-13 expression has been implicated in both physiological and pathological conditions. It has been shown to be essential for normal generation of granulation tissue in mice (20), and it is expressed in various cancers (39)(40)(41)(42). MMP-13 plays predominant roles in rheumatoid arthritis and osteoarthritis, and increased expression of MMP-13 induces osteoarthritis in mice (43).…”