Background: Despite the fact that trastuzumab alongwithotherHER2-targetingdrugshavesignificantlyimprovedthe survival of patients with HER2 overexpression breast cancers (HER2+BC), resistance to trastuzumab is a clinical challenge in HER2+BC. Discerning actionable mechanisms of resistance to trastuzumab remains an important unmet need. WepreviouslyreporteddysregulationofCXCR4involvedintrastuzumab-resistance,butitscausal roleandthe associated mechanismsremainunknown. Methods We established trastuzumab-resistant (TR) human breast cancer HER2+ cell lines by continuously exposing cells to trastuzumab (20 μg/ml) for at least 6 months. CXCR4 expressionwasassessed in TR cells or parental cells with Westernblot.QuantitativedensitometricanalysisofthedensitywasperformedwithAlphaViewSAsoftware.Relevant cell phenotypes were measured, including mammosphere formation, in vitro antibody-dependent cellular cytotoxicity (ADCC) assay, and cell invasion induced by 10% fetal bovine serum with or without 100ng/ml stromal cell-derived factor-1α (SDF-1α, CXCL12), the ligand of CXCR4. ANOVAwasusedtotest differencesbetweenmorethantwogroups,whilethedifferencesbetweentwogroupswereassessedbasedon pairedt-test. Results: To better capture the heterogeneity of HER2+BC, we chose two trastuzumab-sensitive cell lines, BT474 (HER2+/HR+) and SKBR3 (HER2+/HR-) and an intrinsically trastuzumab-resistant cell line, HCC1419 (HER2+/HR-). We found much higher CXCR4 expression levels in cells with intrinsically trastuzumab-resistant cells compared to trastuzumab-sensitive cells. Upregulation of CXCR4 expression was found in each of the acquired TR cell lines compared to their parental cells. Dysregulation of CXCR4 significantly enhanced mammosphere formation and cell invasion (P < 0.001, respectively). SDF-1α induced cell invasion and clumping. Down-regulation of CXCR4 with shRNA significantly increased trastuzumab induced–antibody-dependent cellular cytotoxicity (2.17 folds of control cells, P < 0.01). Targeting CXCR4 with its approved inhibitor AMD3100 significantly decreased mammosphere formation and invasion of HER2+BC with TR (P < 0.01; P < 0.0001 respectively). Conclusion: Our results suggest that the SDF-1-CXCR4 axis plays a critical role in resistance to trastuzumab. Targeting CXCR4 signaling may lead to novel combinational therapies to overcome intrinsic or acquired resistance to trastuzumab in advanced HER2+BC, including postulated effects of trastuzumab on signal transduction, differentiation and immune activation. Citation Format: Liu S, Xie SM, Yang-Kolodji G, Tripathy D. Targeting the tumor microenvironment by CXCR4 inhibition to abrogate trastuzumab resistance in HER2-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-03-04.
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