Integrin α6 β4 on circulating tumor cells of metastatic breast cancer patients

Document Type : Original Article


1 Cancer Prevention Research Center, Isfahan Medical School, Isfahan University of Medical Science, Isfahan, Iran

2 Applied Physiology Research Center, Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran


Background: The detection of circulating tumor cells (CTCs) is prognostic during the disease in women with metastatic breast cancer. Integrins are key role players in nearly every step of cancer progression. In this study, we aimed to analyze integrin alpha6beta4 expression on CTCs isolated from blood samples of patients with advanced breast cancer. Materials and Methods: In this single-center study, peripheral blood samples from 23 breast cancer patients were obtained and analyzed for the presence of CTCs by EasySep™ Direct Human CTC Enrichment Kit combined with subsequent immunocytochemical staining of anti-cytokeratin and anti-epithelial cell adhesion molecules, and β4 integrin on CTCs. Data were correlated with clinicopathological parameters. Results: CTCs were detected in 100% of the patients. The ratio of integrin β4+ CTC was 61% ± 8% of total CTCs. No significant correlation between histopathological parameters and CTC detection was found. Conclusion: Our results demonstrated the importance of α6 β4 integrin expression on CTCs in distant metastasis.


Stewart RL, O'Connor KL. Clinical significance of the integrin α6β4 in human malignancies. Lab Invest 2015;95:976-86.  Back to cited text no. 1
Cooper J, Giancotti FG. Integrin signaling in cancer: Mechanotransduction, stemness, epithelial plasticity, and therapeutic resistance. Cancer Cell 2019;35:347-67.  Back to cited text no. 2
Zhou Z, Qu J, He L, Peng H, Chen P, Zhou Y. α6-Integrin alternative splicing: Distinct cytoplasmic variants in stem cell fate specification and niche interaction. Stem Cell Res Ther 2018;9:122.  Back to cited text no. 3
Krebsbach PH, Villa-Diaz LG. The role of integrin α6 (CD49f) in stem cells: More than a conserved biomarker. Stem Cells Dev 2017;26:1090-9.  Back to cited text no. 4
Li XL, Liu L, Li DD, He YP, Guo LH, Sun LP, et al. Integrin β4 promotes cell invasion and epithelial-mesenchymal transition through the modulation of Slug expression in hepatocellular carcinoma. Sci Rep 2017;7:40464.  Back to cited text no. 5
Cruz-Monserrate Z, Qiu S, Evers BM, O'Connor KL. Upregulation and redistribution of integrin alpha6beta4 expression occurs at an early stage in pancreatic adenocarcinoma progression. Mod Pathol 2007;20:656-67.  Back to cited text no. 6
Giuliano AE, Connolly JL, Edge SB, Mittendorf EA, Rugo HS, Solin LJ, et al. Breast cancer-major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 2017;67:290-303.  Back to cited text no. 7
Rivera-Báez L, Lohse I, Lin E, Raghavan S, Owen S, Harouaka R, et al. Expansion of circulating tumor cells from patients with locally advanced pancreatic cancer enable patient derived Xenografts and functional studies for personalized medicine. Cancers (Basel) 2020;12:1-18.  Back to cited text no. 8
Raymond K, Kreft M, Song JY, Janssen H, Sonnenberg A. Dual Role of alpha6beta4 integrin in epidermal tumor growth: Tumor-suppressive versus tumor-promoting function. Mol Biol Cell 2007;18:4210-21.  Back to cited text no. 9
Lu S, Simin K, Khan A, Mercurio AM. Analysis of integrin beta4 expression in human breast cancer: Association with basal-like tumors and prognostic significance. Clin Cancer Res 2008;14:1050-8.  Back to cited text no. 10
Diaz LK, Cristofanilli M, Zhou X, Welch KL, Smith TL, Yang Y, et al. Beta4 integrin subunit gene expression correlates with tumor size and nuclear grade in early breast cancer. Mod Pathol 2005;18:1165-75.  Back to cited text no. 11
Tagliabue E, Ghirelli C, Squicciarini P, Aiello P, Colnaghi MI, Ménard S. Prognostic value of alpha 6 beta 4 integrin expression in breast carcinomas is affected by laminin production from tumor cells. Clin Cancer Res 1998;4:407-10.  Back to cited text no. 12
Gilcrease MZ, Kilpatrick SK, Woodward WA, Zhou X, Nicolas MM, Corley LJ, et al. Coexpression of alpha6beta4 integrin and guanine nucleotide exchange factor Net1 identifies node-positive breast cancer patients at high risk for distant metastasis. Cancer Epidemiol Biomarkers Prev 2009;18:80-6.  Back to cited text no. 13
Ruan S, Lin M, Zhu Y, Lum L, Thakur A, Jin R, et al. Integrin β4-targeted cancer immunotherapies inhibit tumor growth and decrease metastasis. Cancer Res 2020;80:771-83.  Back to cited text no. 14