The Role Of Kindlin-2 In The Formation Of Breast Lesions Stiffness And Its Molecular Mechanism

The incidence and mortality of breast cancer is on the rise in China,which affects women’s health and life quality and accurate,timely diagnosis is very important for millions of patients.Stiffness is a key characteristic of tissues and organs,which has historically served as the basis for clinical examinations,such as palpation,especially in breast abnormalities.It had first been introduced to evaluate tissue stiffness in 1997.Shear wave elastography(SWE)is a new method of elastography which can provide reproducible,quantitative data.Kindlin-2,a member of Kindlins protein family,was first discovered from Caenorhabditis elegans,and subsequently found in humans as a protein with similar structure and function.Kindlin-2 is evolutionarily conserved and widely expressed as an important regulator of integrin mediated extracellular matrix(ECM)interaction.Kindlin-2 is also reported to be an important factor in the regulation of podocyte-matrix adhesion,and matrix deposition of fibronectin and collagen type I.Other studies found that Kindlin-2 could activate the TGF-β/Smad signaling,contributing to the pathogenesis of pancreatic ductal adenocarcinoma and tubulointerstitial fibrosis by stimulating the production of collagen.This study investigated the relationship between quantitative parameters of shear wave elastography(SWE,maximum elasticity[Emax],minimum elasticity[Emin],mean elasticity[Emean]),collagen intensity and Kindlin-2 expression in benign and malignant breast nodules,and if Kindlin-2 expression is related with lymph node metastasis.A total of 102 breast nodules from 102 patients were included in our study who underwent conventional ultrasound and shear wave elastography before surgery or core needle biopsy.There was a significant difference between benign and malignant breast nodules in Emax,Emean,collagen intensity and Kindlin-2 expression,but it had no difference in Emin.Collagen intensity and Kindlin-2 expression both correlated positively with Emax,but not with Emean.Among 38 malignant breast nodules,the average Emax of the metastasis group was higher than that of the non-metastasis group,but it had no statistical significance.Compared with the non-metastasis group,Kindlin-2 expression was considerably higher in the metastasis group.However,there was no difference in collagen intensity between the metastasis group and the non-metastasis group.Moreover,the expression of p-FAK and p-Smad2 which are respectively important proteins of integrin signaling and TGF-βsignaling were both higher in malignant nodules than that of benign nodules.Meanwhile,the expression of both p-FAK and p-Smad2 in malignant nodules with metastasis was higher than that without metastasis.In conclusion,Kindlin-2 and collagen might contribute to breast nodule stiffness and promote lymph nodules metastasis through integrin signaling and TGF-βsignaling.In breast cancer,overexpression of Kindlin-2 might be a risk factor for lymph node metastasis.