Expression Of Integrinβ1 And Kindlin-2 In Invasive Micropapillary Carcinoma Of The Breast

ObjectiveInvasive micropapillary carcinoma(IMPC) of the breast is a special subtype of invasive breast cancer, and it is rare in clinical. The tumor cells always polarity reversed, and collective invasion. compared with other types of breast cancer patients, IMPC patients are more prone to recurrence and distant metastasis, and also with a poor prognosis. This study aims to investigate the location and expression of the integrinβ1 and kindlin-2 protein in IMPC and invasive ductal carcinoma not otherwise specified(IDC-NOS), their relationship with clinicopathological features and prognosis were analyzed. In order to preliminary clarify the reason why the polarity is reversed in IMPC, and provide new ideas for understanding the pathogenesis, clinical progression and prognosis of the IMPC.MethodsThe location and expression of integrinβ1 and kindlin-2 were determined by immunohistochemical staining in 99 cases of IMPC and 132 cases of IDC-NOS. Both IMPC and IDC-NOS were undergoing without preoperative chemotherapy and radiotherapy. The correlation of integrinβ1 and kindlin-2 expression between the two proteins and with the clinicopathologic characteristics, which include the prognosis patients were determined.Results1. Compared with the control group of IDC-NOS, IMPC were larger in size(t=3.448, P=0.001), higher p TNM stages(H=17.211, P<0.001), had a higher lymph node metastasis rate(χ2=8.596, P=0.003), and exhibited increased lymphovascular invasion(χ2=19.564, P<0.001) and extranodal extension(χ2=11.118, P=0.001), differences were statistically significant.2. According to the percentage of IMPC component in the whole tumor, the 99 cases of IMPC were divided into four groups: <25% of the 26 cases, 25%~49% of the 15 cases, 50%~75% of the 17 cases, > 75 % of the 41 cases. The Spearman rank correlation analysis showed that the expression of integrinβ1(P=0.564) and kindlin-2(P=0.520) had no difference between the four groups.3. Integrinβ1 was mainly expressed in the membrane or plasma of tumor cells, and it is loss of or reduction in the outer margin, but not inside the micropapillarystructure of IMPC. But it is expressed extensively in IND-NOS. kindlin-2 was mainly expressed in cytoplasm. In this study integrinβ1 expressed positively 30.3%(30/99) in IMPC, significantly higher than IDC-NOS group 16.7%(22/132). And the kindlin-2 expressed positively 64.6%(64/99), significantly higher than IDC-NOS group 50.8%(67/132). Both differences were statistically significant.4. The expression of integrinβ1 is correlation with kindlin-2 in IMPC(r=0.212, P=0.035), but not in the IDC-NOS group(P>0.05).5. The expression of integrinβ1 had a significant positive correlation with human epidermal growth factor receptor 2(HER2)(r=0.426, P<0.001), E-cadherin(E-CD)(r=0.217, P=0.031) and lymph node metastasis(r=0.207, P=0.040), but had no correlation with p TNM stages(P>0.05). The expression of kindlin-2 had a significant positive correlation with HER2(r=0.212, P=0.035), E-CD(r=0.218, P=0.030), lymph node metastasis(r=0.294, P=0.003) and p TNM stages(r=0.245, P=0.015). No correlation was found between integrinβ1 or kindlin-2 and the patient’s age, tumor size, menopausal status, estrogen receptor, progesterone receptor, extranodal extension, or lymphovascular invasion.6. Kaplan-Meier survival analysis shown that the IMPC patients with integrinβ1 positive expression had a lower disease-free survival(DFS) and overall survival(OS) compared to the same patients with integrinβ1 negative expression(log-rank test, PDFS=0.046, POS= 0.020). This was similar in IDC-NOS patients(log-rank test, PDFS=0.047, POS= 0.037). But the expression of kindlin-2 had no correlation with DFS and OS whether in the IMPC or IDC-NOS(P>0.05). Comprehensive analysis found that the patients with the two proteins positive expression were significantly lower than their expression were negative or anyone positive patients in IMPC(PDFS=0.026, POS= 0.012) and IDC-NOS(PDFS=0.003, POS= 0.007). Cox proportional hazard regression model analysis showed that the results were not statistically significant whether in the IMPC or IDC-NOS.Conclusion1. IMPC had a higher lymph node metastasis and lymphovascular invasion rate, and also had a poor prognosis.2. The expression of integrinβ1 and kindlin-2 in IMPC were not significantly associated with the percentage of IMPC components in the whole tumor.3. Integrinβ1 was polarity expression in IMPC, and it was over-expressed comparedwith IDC-NOS, and kindlin-2 also had a higher expression rate in IMPC. This may suggested that the two proteins play a key role in IMPC progression.4. The formation of IMPC with polarity reversed may be related to the synergistic effect of integrinβ1 and kindlin-2.5. Integrinβ1 and kindlin-2 may played an important role in the high invasion biology characteristic of IMPC, and the synergistic effect of the two proteins may promoted malignant progression of IMPC through epithelial-mesenchymal transition(EMT).6. The relationship between the survival of breast cancer patients and the expression of integrinβ1 or kindlin-2 was still controversial. Comprehensive analysis showed that patients had worst prognosis when the two proteins both positive. This suggesting that synergistic effect of the two proteins may be the factors affecting the prognosis of patients.