Expression of the C-Met/HGF receptor in human breast carcinoma: Correlation with tumor progression

Beviglia, Lucia; Matsumoto, Kentaro; Lin, C. C.; Ziober, Barry L.; Kramer, Randall H.

doi:10.1002/(sici)1097-0215(19970620)74:3<301::aid-ijc12>3.0.co;2-e

Cited by 141 publications

(61 citation statements)

References 14 publications

(9 reference statements)

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“…The results showed that HGF did not influence cancer cell viability and proliferation (Figure S3C–3D). These data were consistent with previous report [38]. Moreover, the HGF-induced invasion was inhibited by PKCζ-siRNAs, as well as the effect of PSζ.…”

Section: Resultssupporting

confidence: 93%

HGF-Induced PKCζ Activation Increases Functional CXCR4 Expression in Human Breast Cancer Cells

et al. 2012

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The chemokine receptor CXCR4 and its ligand CXCL12 have been shown to mediate the metastasis of many malignant tumors including breast carcinoma. Interaction between hepatocyte growth factor (HGF) and the Met receptor tyrosine kinase mediates development and progression of cancers. HGF is able to induce CXCR4 expression and contributes to tumor cell invasiveness in breast carcinoma. However, the mechanism of the CXCR4 expression modulated by c-Met-HGF axis to enhance the metastatic behavior of breast cancer cells is still unclear. In this study, we found that HGF induced functional CXCR4 receptor expression in breast cancer cells. The effect of HGF was specifically mediated by PKCζ activity. After transfection with PKCζ-siRNA, the phosphorylation of PKCζ and CXCR4 was abrogated in breast cancer cells. Interference with the activation of Rac1, a downstream target of HGF, prevented the HGF-induced increase in PKCζ activity and CXCR4 levels. The HGF-induced, LY294002-sensitive translocation of PKCζ from cytosol to plasma membrane indicated that HGF was capable of activating PKCζ, probably via phosphoinositide (PI) 3-kinases. HGF treatment also increased MT1-MMP secretion. Inhibition of PKCζ, Rac-1 and phosphatidylinositol 3-kinase may attenuate MT1-MMP expression in cells exposed to HGF. Functional manifestation of the effects of HGF revealed an increased ability for migration, chemotaxis and metastasis in MDA-MB-436 cells in vitro and in vivo. Our findings thus provided evidence that the process of HGF-induced functional CXCR4 expression may involve PI 3-kinase and atypical PKCζ. Moreover, HGF may promote the invasiveness and metastasis of breast tumor xenografts in BALB/c-nu mice via the PKCζ-mediated pathway, while suppression of PKCζ by RNA interference may abrogate cancer cell spreading.

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Section: Resultssupporting

confidence: 93%

HGF-Induced PKCζ Activation Increases Functional CXCR4 Expression in Human Breast Cancer Cells

et al. 2012

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“…ERα, one of the most important targets in human breast cancer therapy, is expressed in T-47D cells, whereas the TNBC cells lack the expression of ERα due to epigenetic silencing [41]. On the other hand, c-Met is overexpressed in the TNBC MDA-MB-231 and MDA-MB-468 cells, while it is absent in T-47D cells [42]. …”

Section: Resultsmentioning

confidence: 99%

Novel c-Met inhibitory olive secoiridoid semisynthetic analogs for the control of invasive breast cancer

Mohyeldin

Busnena

Akl

et al. 2016

European Journal of Medicinal Chemistry

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Dysregulated receptor tyrosine kinase c-Met and its ligand HGF is valid and attractive molecular target for therapeutic blockade in cancer. Inspired by the chemical structure of the naturally occurring olive secoiridoid (-)-oleocanthal (1) and its documented anticancer activity against c-Met-dependent malignancies, a previous study reported tyrosol sinapate (4) as a c-Met inhibitor hit. This study reports additional semisynthetic optimization and SAR of 4 to improve its selective activity against c-Met-dependent breast cancer by increasing its capacity to inhibit c-Met phosphorylation. Forty-three compounds (5-47) were synthesized, among which the novel analog homovanillyl sinapate (HVS-16) was distinguished for its remarkable activity. HVS-16 substantially impaired c-Met-mediated proliferation, migration, and invasion across human breast cancer cell lines in two- and three-dimensional culture systems, while similar treatment doses were found to have effect neither on the non-tumorigenic human mammary epithelial cell growth nor on the c-Met independent breast cancer cell viability. HVS-16 showed a dose-dependent inhibition of ligand-mediated c-Met activation in human breast cancer cells. Docking studies revealed that HVS-16 fits very well inside c-Met crystal structures, satisfying critical interactions at the ATP binding site. This study identified important structural pharmacophoric features in HVS-16 and correlated its postulated binding pose with c-Met kinase assay data that would guide future olive secoiridoid bioisostere lead design. Results presented herein suggest HVS-16 as a promising c-Met inhibitor validated hit with potential to control invasive breast malignancies with aberrant c-Met activity.

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“…One of the negatively regulated miR-34b target genes is receptor tyrosine kinase c-MET [58]. Increased levels of receptor tyrosine kinase c-MET have been shown to lead to enhanced invasion and metastasis in a number of cancers including breast [59] and have recently been associated with progression of basal-like breast cancer a subtype more common among younger African American women [60]. Thus miR-34b acts as a tumor suppressor gene by down-regulating receptor tyrosine kinase c-MET.…”

Section: Discussionmentioning

confidence: 99%

Association of germline microRNA SNPs in pre-miRNA flanking region and breast cancer risk and survival: the Carolina Breast Cancer Study

Bensen

Tse

Nyante

et al. 2013

Cancer Causes Control

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Purpose Common germline variation in the 5′ region proximal to precursor (pre-) miRNA gene sequences is evaluated for association with breast cancer risk and survival among African Americans and Caucasians. Methods We genotyped 9 single nucleotide polymorphisms (SNPs) within 6 miRNA gene regions previously associated with breast cancer, in 1972 cases and 1776 controls. In a race-stratified analysis using unconditional logistic regression, odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate SNP association with breast cancer risk. Additionally, hazard ratios (HR) for breast cancer-specific mortality were estimated. Results 2 miR-185 SNPs provided suggestive evidence of an inverse association with breast cancer risk (rs2008591, OR = 0.72 (95% CI = 0.53 – 0.98, p-value = 0.04) and rs887205, OR = 0.71 (95% CI = 0.52 – 0.96, p-value = 0.03), respectively) among African Americans. Two SNPs, miR-34b/34c (rs4938723, HR = 0.57 (95% CI = 0.37 – 0.89, p-value = 0.01)) and miR-206 (rs6920648, HR = 0.77 (95% CI = 0.61 – 0.97, p-value = 0.02)), provided evidence of association with breast cancer survival. Further adjustment for stage resulted in more modest associations with survival (HR = 0.65 (95% CI = 0.42 – 1.02, p-value = 0.06 and HR = 0.79 (95% CI = 0.62 – 1.00, p-value = 0.05, respectively). Conclusions Our results suggest that germline variation in the 5' region proximal to pre-miRNA gene sequences may be associated with breast cancer risk among African Americans and breast cancer-specific survival generally, however further validation is needed to confirm these findings.

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Expression of the C-Met/HGF receptor in human breast carcinoma: Correlation with tumor progression

Cited by 141 publications

References 14 publications

HGF-Induced PKCζ Activation Increases Functional CXCR4 Expression in Human Breast Cancer Cells

HGF-Induced PKCζ Activation Increases Functional CXCR4 Expression in Human Breast Cancer Cells

Novel c-Met inhibitory olive secoiridoid semisynthetic analogs for the control of invasive breast cancer

Association of germline microRNA SNPs in pre-miRNA flanking region and breast cancer risk and survival: the Carolina Breast Cancer Study

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