The Clinical Significance Of Hepatocyte Growth Factor,β-catenin And HER2 Expression In Invasive Breast Cancer

Objective:Currently, breast cancer is the most common malignancy threatening life and health of women with an arising incidence and involving young female tendency. Targeted therapy, neoadjuvant therapy, surgery and endocrine therapy have significantly improved the five year survival rate and life quality of HER2 positive breast cancer patients. Nevertheless, the overall mortality remains high and resistance to chemotherapy and Herceptin leads to poor prognosis of patients with HER2 positive breast cancer.Hepatocyte growth factor (HGF) is a multi-functional cytokine which could promote cell division, migration and induce proliferation of vascular endothelial cells. Besides, HGF/c-met signaling pathway could reduce intercellular adhesion by phosphorylation of the tyrosine residues of β-catenin and thereby promoting tumor invasion and metastasis.This study is aim to explore the expression of HGF and P-catenin in invasive breast cancer, their potential roles in the progression and metastasis of breast cancer and their correlation with HER2 positive expressionMaterials and Methods:A total of 102 patients who underwent radical mastectomy for breast cancer between June 1st 2007 and June 1st 2012 were recruited. All these patients have full clinical information and none of them has experienced chemotherapy before surgery.20 samples from patients with breast adenosis were taken as benign lesion control. Four tissue microarray slides were constructed based on these samples.All 102 patients with invasive breast cancer are female, age from 34 to 78 with a median age of 52 years old.53 out of 102 patients were left breast cancer while the others were right breast cancer. Based on WHO histological grading criteria,6 cases belonged to grade 1,72 cases belonged to grade 2 and 24 cases belonged to grade 3.In tumor size:49 cases were tumor size≥2cm while the other 53 cases with tumor size <2cm. There were 46 out of 102 cases with lymph node metastasis, other patients were lymph node negative. IHC Envision two step method was performed to detect the expression of HGF, P-catenin and C-erb-B2 (HER2) in tissue samples of breast cancer and breast adenosis FISH was employed for further determination of HER2 status of patients with HER2 (2+).According to previous studies, HGF status was defined as brown granular staining in stroma cells, tumor cells and epithelial cells of breast with no background staining. Each sample had a duplicate section on tissue microarray and was observed at HPF (x400). Based on staining intensity and percentage of positive cells, HGF positive result was defined as≥20% positive tumor cells while HGF negative was defined as<20% positive tumor cells. According to previous studies, β-catenin positive in membrane (>70%) was defined as normal expression, otherwise indicated loss of its expression. Cytoplasm or nuclei positivity (>10%) was defined as aberrant expression. HER2 status was defined according to ASCO HER2 test guideline recommendations. Briefly, IHC HER2 (0 or 1+) was defined as negative, whereas HER2 (3+) was defined as positive. For HER 2(2+) patients, FISH needed to be performed.All statistical analyses were performed using SPSS software version 17.0. Rowxcolumn χ2 test and fourfold table χ2 test were employed in this study. Categorical data was demonstrated as ratio, and P<0.05 was defined as statistically significant.Results:There were 64 HGF positive cases in 102 patients with invasive breast cancer, in which 21 (32.8%) HGF positive cases were HER2 positive while the other 43 (67.2%) cases were HER2 negative group. Interestingly,21 out of 22 HER2 positive patients were HGF positive (95.5%). The correlation of HGF with HER2 positive expression cases had statistically difference (χ2=12.839, P<0.05). HGF positive rate in lymph node positive group (41 cases,89.1%) was significantly higher than that of lymph node negative group (23 cases,41.1%) with χ2=24.954 (P<0.05). HGF positive cases in histological grade 1,2 and 3 breast invasive cancer were 5 (7.8%),46 (71.9%) and 11 (20.3%), respectively. There were no statistical difference among three groups (χ2=1.844, P>0.05). Besides, HGF expression positivity was not correlated with tumor size (≥2cm or <2cm,33 (67.3%) vs 31 (58.5%), χ2=0.854, P>0.05). The above results showed that HGF expression was correlated with HER2 positivity and lymph node metastasis. However, HGF expression had no correlation with tumor size or histological grade.β-catenin was aberrantly expressed in 21 out of 22 HER2 positive patients (95.5%) which significantly higher that HER2 negative group (43 positive cases,54.8%) with χ2=12.843 (P<0.05). Aberrant expression rate of β-catenin in lymph node positive group (36 cases,78.3%) was significantly higher than that of lymph node negative group (28 cases,50.0%) with χ2=10.881 (P<0.05).β-catenin aberrant expression cases in histological grade 1,2 and 3 breast cancer were 4 (6.3%),48 (75.0%) and 12 (18.8%), respectively. There were no statistical difference among three groups (χ2=2.862, P>0.05). Besides,β-catenin aberrant expression was not associated with tumor size (≥2cm or< 2cm,33 (51.6%) vs 31 (48.4%),χ2=0.934, P>0.05). The above result showed that the expression of P-catenin was closely associated with HER2 positivity and lymph node metastasis, while it was not correlated with tumor size or histological grade.There were 47 patients with β-catenin aberrant expression in 64 HGF positive breast cancer accounting for 73.4%, which was significantly higher than that in P-catenin negative group (16 cases,25%) and normal membrane positive group (1 case, 1.6%) with χ2=9.744 (P<0.05). These results indicated that HGF expression was closely associated with β-catenin aberrant expression.Conclusion:1. HGF was up-regulated in invasive breast cancer compared with breast adenosis. HGF was closely associated with HER2 positive expression and lymph nodes metastases. Correlation with tumor size or histological grade was not observed.2. β-catenin was aberrant expression in invasive breast cancer compared with normal expression in breast adenosis. β-catenin were closely associated with HER2 positive expression and lymph nodes metastases. Correlation with tumor size or histological grade was not observed.3. HGF expression was positively correlated with β-catenin expression in invasive braest cancer.