The Hepatocyte Growth Factor Regulatory Factors in Human Breast Cancer

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Abstract
Hepatocyte growth factor (HGF) stimulates tumor cell-cell interactions, matrix adhesion, migration, invasion, and angiogenesis. This factor is produced as an inactive precursor called pro-HGF, which requires proteolytic conversion, by HGF activator (HGFA) and matriptase, to evoke a biological response. Two new HGFA inhibitors, HAI-1 and HAI-2, inhibit the generation of biologically active HGF, through their interaction with HGFA. This study determined the expression of this HGF regulatory system in breast cancer. We examined HGF, the HGF receptor (c-Met), HGFA, matriptase, and the activation inhibitors (HAI-1 and HAI-2), tissues from patients with breast cancer. Breast cancer tissue (n = 100) and normal background tissue (n = 20) was obtained immediately after surgery. The median follow-up for the patients was 72 months. HGF, c-Met, HGFA, matriptase-1, HAI-1, and HAI-2 expression was quantified using real-time quantitative PCR. The distribution of these factors in mammary tissues was also examined through immunohistochemistry. The breast cancer specimens expressed a significantly higher level of HGF, c-Met, HGFA, HAI-1, and HAI-2, but not matriptase, compared with the normal background tissues. Tumor tissues from node-positive patients expressed a higher level of HGFA than from the patients without nodal involvement. Interestingly, HAI-2 was expressed to a lower degree in positive nodes than that of the node-negative breast cancer tissues. HAI-1 and HAI-2 were both significantly reduced in grade 3 tumors compared with the well-differentiated tumors. In addition, on comparison of Tumor-Node-Metastasis (TNM) classification groups, HAI-2 was also found to be statistically lower in the TNM 3 breast cancer group when compared with TNM groups 1 and 2, thus associated with a poor prognosis. This study shows that there are aberrant levels of HGF, c-Met, HGFA, HAI-1, and HAI-2 expressed in breast cancer tissues compared with background breast tissue. HAI-1 and HAI-2 are expressed to a significantly lower level in poorly differentiated breast tumors, and HAI-2 is also inversely correlated with nodal involvement and tumor spread. Overall a low level of HAI-2 in the breast cancer tissues was associated with an overall poor outlook. Therefore, the HGF regulatory system may have an important role in the progression of breast cancer.

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