Amplification or overexpression of HER2/neu, a 185 kDa transmembrane tyrosine kinase receptor, has been reported in 20-30% of invasive breast cancers (IBCs) . It predicts a more aggressive clinical course such as a transition from in situ growth to invasion , aggressive disease progression and poor treatment response [3–5]. In addition, it has been shown that there is a high concordant HER2/neu status in paired primary tumor and distant metastatic lesions on analysis by both immunohistochemistry (IHC) and by fluorescence in situ hybridization (FISH) [6–9]. Therefore, HER2/neu status is an important diagnostic and prognostic biomarker and is also one of the most dependable criteria for the use of trastuzumab-based chemotherapy to treat breast cancer.
In addition to HER2/neu status of the tumor tissue, the extracellular domain (ECD) of HER2 (HER2 ECD), which is shed from the HER2/neu receptor after a proteolysis process, has been shown to show a better correlation with tumor burden, treatment response, disease-free status and overall survival than the full-length HER2/neu . However, certain clinical studies have not supported baseline serum HER2 ECD as a reliable predictor of tumor progression, treatment response, duration of response, or time to progression in advanced/metastatic breast cancer [11, 12]. Thus, in agreement with the 2007 and 2009 American Society of Clinical Oncology guidelines on the use of biomarkers in breast cancer [11, 13], there is currently insufficient evidence to support the use of serum HER-2 ECD in the routine management of individual patients with breast cancer.
It has been demonstrated that extracellular matrix remodeling proteinases, such as matrix metalloproteinases (MMPs), play a key role in the invasion and metastasis of cancer cells [14–16]. Recent studies have indicated that members of a zinc-dependent family of proteinases related to the MMPs, namely disintegrin and metalloproteinases (ADAMs), are also involved in cancer progression . A major level of control MMP functions occurs via their interaction with specific tissue inhibitors of metalloproteinases (TIMPs) . Similar to MMPs, ADAM family members are also inhibited by specific TIMPs . Among known MMPs and ADAMs, ADAM-10 has been shown to play an important role in the shedding of dozens of substrates that drive cancer progression, including HER2/neu [19, 20]. Furthermore, HER2 ECD shedding can be inhibited by broad-spectrum metalloprotease inhibitors such as TAPI, batimastat, and TIMP-1 [19, 21]. However, elevated TIMP-1 expression in human cancers, including breast cancer, has been associated with a decreased time to recurrence and a lower overall survival [22–26].
It is well known that there are significant ethnic disparities between western and eastern countries in terms of breast cancer with respect to cancer incidence, the frequency of BRCA1 and BRCA2 mutation, tumor biology and molecular subtypes [27–29]. In this context, information on the role of serum HER2 ECD in Asian breast cancer women is limited. Therefore, this study was performed to explore the relationships between serum HER2 ECD level, serum TIMP-1 level and clinical outcomes. Since MMP-2 and MMP-9 (gelatinase A and B) have been shown to be associated with breast cancer, expression of HER2/neu, and an unfavorable prognosis [15, 16] and because TIMP-2 also seems to have cell growth promoting and anti-apoptotic activity , serum MMP-2, MMP-9 and TIMP-2 were also included in the present analysis.