The Three Receptor Tyrosine Kinases c-KIT, VEGFR2 and PDGFRα, Closely Spaced at 4q12, Show Increased Protein Expression in Triple-Negative Breast Cancer

Abstract

BackgroundTriple-negative breast cancer (TNBC) is a heterogeneous subgroup of breast cancer with poor prognosis and no targeted therapy available. Receptor tyrosine kinases (RTKs) are emerging targets in anticancer therapy and many RTK-inhibiting drugs are currently being developed. The aim of this study was to elucidate if there is a correlation between the protein expression of three RTKs c-KIT, VEGFR2 and PDGFRα, their gene copy number, and prognosis in TNBC compared to non-TNBC.MethodsTumor tissue samples from patients diagnosed with primary breast cancer were stained with immunohistochemistry (IHC) for protein assessment, and with fluorescence in situ hybridization (FISH) for gene copy number determination. Breast cancer mortality (BCM), measured from the date of surgery to death, was used as endpoint.ResultsThe cohort included 464 patients, out of which 34 (7.3%) had a TNBC. High expression of the three RTKs was more common in TNBC compared to non-TNBC: c-KIT 49% vs. 10% (P<0.001), PDGFRα 32% vs. 19% (P = 0.07) and VEGFR2 32% vs. 6% (P<0.001). The odds ratio (OR) of c-KIT, VEGFR2 and PDGFRα positivity, adjusted for tumor characteristics, was 6.8, 3.6 and 1.3 times higher for TNBC than for non-TNBC. 73.5% of the TNBC had high expression of at least one of the three investigated receptors, compared to 30.0% of the non-TNBC (P<0.001). Survival analysis showed no significant difference in BCM for TNBC patients with high vs. low c-KIT, PDGFRα or VEGFR2 protein expression. 193 (42%) tumors were evaluated with FISH. No correlation was seen between increased gene copy number and TNBC, or between increased gene copy number and high protein expression of the RTK.Conclusionc-KIT, VEGFR2 and PDGFRα show higher protein expression in TNBC compared to non-TNBC. Further investigation clarifying the importance of these RTKs in TNBC is encouraged, as they are possible targets for anticancer therapy.

Prognostic significance of CD117 expression and TP53 missense mutations in triple-negative breast cancer

“…Nuclear staining in >1% of tumor cell nuclei was considered a positive indication of the presence of ER and PR. Immunostaining for HER2 and CD117 ( 11 , 21 ) was graded according to the percentage of cells: 0, none; 1+, <10% staining weak and incomplete; 2+, ≥10%, staining weak to moderate; and 3+, ≥10% strong staining. HER2 immunostaining was considered positive if graded 3+, or if gene amplification was confirmed by fluorescence in situ hybridization (FISH) in patients exhibiting 2+ immunostaining.…”

“…Immunohistochemical staining has revealed that CD117 protein is overexpressed in primary malignant tumors, including operable esophageal squamous cell carcinoma and vulvar melanoma, and may be a valuable prognostic marker in esophageal squamous cell carcinoma ( 8 ). However, the results of studies concerning the prognostic significance of CD117 in patients with breast cancer or TNBC are conflicting: Kashiwagi et al have suggested that CD117 protein is associated with poor prognosis ( 9 ), whereas others identified no significant association between CD117 and prognosis in breast cancer or TNBC ( 10 , 11 ).…”

Current advances in biomarkers for targeted therapy in triple-negative breast cancer

“…c-Kit may be expressed in ~25%–45% of TNBC, 64 , 65 but studies disagree as to whether c-Kit levels predict the overall survival of TNBC patients. 10 , 66 , 67 A Phase II trial examined sunitinib (a targeted agent that inhibits c-Kit as well as multiple other kinases) as monotherapy in patients with advanced TNBC as compared to standard chemotherapeutic regimen and found that sunitinib was not an effective treatment. 68 Because of the controversial evidence of c-Kit in TNBC, more studies are needed in order to determine its potential usefulness as a TNBC biomarker.…”

CD117 expression is correlated with poor survival of patients and progression of lung carcinoma:a meta-analysis with a panel of 2645 patients

“…OneofpotentialmarkersisCD117,atransmembraneproteinthatreceivesthemessagefromastemcell factor (SCF). CD117 protein is encoded by the proto-oncogene c-kit and belongs to the tyrosine kinasereceptorfamily [20,21].Recentstudieshave suggestedthatCD117proteinisaberrantlyregulatedinmalignanciesofthesalivarygland [22],retinoblastoma [23],endometrium [24],papillarythyroid [25],andbreast [26].CD117isalsoanauthoritative protein in the diagnosis of gastrointestinal stromal tumours (GIST), where it generally shows positive expression [27].Severalstudiesthatconcentratedon CD117 protein in lung cancer showed that CD117 proteinexpressionhadnoeffectonprogressionand prognosisoflungcarcinoma [20,28],whereasother studies have suggested that CD117 protein could beusedasabiomarkerforlungcarcinoma [29,30,31].Thepurposeofthepresentcomprehensivemeta-analysis was to clarify the relationship between CD117proteinandlungcarcinoma.…”