The Hepatocyte Growth Factor Regulatory Factors in Human Breast Cancer

Abstract

Purpose: 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.Experimental Design: 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.Results: 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.Conclusions: 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.

Delphinidin inhibits cell proliferation and invasion via modulation of Met receptor phosphorylation

“…The involvement of hepatocyte growth factor (HGF)-Met signaling in breast cancer biology has been well characterized (Parr et al, 2004). Increased cell proliferation, survival, motility, and extracellular matrix degradation resulting from the pathway activation contributes to tumor growth, invasiveness, and metastasis (Parr et al, 2004).…”

“…Increased cell proliferation, survival, motility, and extracellular matrix degradation resulting from the pathway activation contributes to tumor growth, invasiveness, and metastasis (Parr et al, 2004). In fact, high levels of HGF and Met expression associated with invasive human breast cancer have been considered as possible indicators of earlier recurrence and shortened survival in these patients (Lindemann et al, 2007).…”

The Role of HGF/c-Met Pathway Signaling in Human Medulloblastoma

“…The experimental studies using medulloblastoma cells transfected with SPINT2 showed decreased proliferation, migration and anchorage-independent growth in vitro and increased survival times in mouse xenografts (Kongkham et al, 2008). Although SPINT2 downregulation has already been implicated in other human cancers (Dong et al, 2010;Morris et al, 2005;Parr et al, 2004) this was the first report to establish its role in medulloblastoma pathogenesis. Binning et al showed that HGF and Shh cooperate to transform cerebellar neural progenitors in transgenic mice, leading to medulloblastoma initiation and growth (Binning et al, 2008).…”

Sequence and Conformational Specificity in Substrate Recognition

“…Activated HGF/SF binds to its receptor tyrosine kinase MET to induce dimerization and initiate phosphorylation cascades leading to comprehensive cellular changes that, in the deregulated context of cancer, drive malignant transformation and progression (73). HAI2 has been found to be a natural tumor suppressor in renal cell carcinoma (74), breast cancer (75,76), and prostate cancer (77,78), the loss of which leads to tumor growth and progression attributable at least in part to increased MET signaling. We have found mesotrypsin to be up-regulated with progression in prostate cancers and to contribute to invasion and metastasis (10), and it is highly plausible that these activities of mesotrypsin may be mediated at least in part through cleavage and inactivation of HAI2, with resulting increases in HGF/SF activation and MET signaling.…”