Journal article
Cytokine Receptor CXCR4 Mediates Estrogen-Independent Tumorigenesis, Metastasis, and Resistance to Endocrine Therapy in Human Breast Cancer
Cancer research (Chicago, Ill.), Vol.71(2), pp.603-613
01/15/2011
DOI: 10.1158/0008-5472.CAN-10-3185
PMCID: PMC3140407
PMID: 21123450
Abstract
Estrogen independence and progression to a metastatic phenotype are hallmarks of therapeutic resistance and mortality in breast cancer patients. Metastasis has been associated with chemokine signaling through the SDF-1-CXCR4 axis. Thus, the development of estrogen independence and endocrine therapy resistance in breast cancer patients may be driven by SDF-1-CXCR4 signaling. Here we report that CXCR4 overexpression is indeed correlated with worse prognosis and decreased patient survival irrespective of the status of the estrogen receptor (ER). Constitutive activation of CXCR4 in poorly metastatic MCF-7 cells led to enhanced tumor growth and metastases that could be reversed by CXCR4 inhibition. CXCR4 overexpression in MCF-7 cells promoted estrogen independence in vivo, whereas exogenous SDF-1 treatment negated the inhibitory effects of treatment with the anti-estrogen ICI 182,780 on CXCR4-mediated tumor growth. The effects of CXCR4 overexpression were correlated with SDF-1-mediated activation of downstream signaling via ERK1/2 and p38 MAPK (mitogen activated protein kinase) and with an enhancement of ER-mediated gene expression. Together, these results show that enhanced CXCR4 signaling is sufficient to drive ER-positive breast cancers to a metastatic and endocrine therapy-resistant phenotype via increased MAPK signaling. Our findings highlight CXCR4 signaling as a rational therapeutic target for the treatment of ER-positive, estrogen-independent breast carcinomas needing improved clinical management. Cancer Res; 71(2); 603-13. (C) 2010 AACR.
Details
- Title: Subtitle
- Cytokine Receptor CXCR4 Mediates Estrogen-Independent Tumorigenesis, Metastasis, and Resistance to Endocrine Therapy in Human Breast Cancer
- Creators
- Lyndsay V. Rhodes - Louisiana State University Health Sciences Center New OrleansSarah P. Short - Vanderbilt UniversityNicole F. Neel - Vanderbilt UniversityVirgilio A. Salvo - Louisiana State University Health Sciences Center New OrleansYun Zhu - Louisiana State University Health Sciences Center New OrleansSteven Elliott - Tulane UniversityYongkun Wei - Tulane UniversityDihua Yu - The University of Texas MD Anderson Cancer CenterMenghong Sun - Tulane UniversityShannon E. Muir - Tulane UniversityJuan P. Fonseca - Tulane UniversityMelyssa R. Bratton - Louisiana State University Health Sciences Center New OrleansChris Segar - Tulane UniversitySyreeta L. Tilghman - Tulane UniversityTammy Sobolik-Delmaire - Tulane UniversityLinda W. Horton - Tulane UniversitySnjezana Zaja-Milatovic - Tulane UniversityBridgette M. Collins-Burow - Tulane UniversityScott Wadsworth - Tulane UniversityBarbara S. Beckman - Tulane UniversityCharles E. Wood - Tulane UniversitySuzanne A. Fuqua - Tulane UniversityKenneth P. Nephew - Tulane UniversityPaul Dent - Virginia Commonwealth UniversityRebecca A. Worthylake - Tulane UniversityTyler J. Curiel - Tulane UniversityMien-Chie Hung - Tulane UniversityAnn Richmond - Tulane UniversityMatthew E. Burow - Tulane University
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.71(2), pp.603-613
- Publisher
- Amer Assoc Cancer Research
- DOI
- 10.1158/0008-5472.CAN-10-3185
- PMID
- 21123450
- PMCID
- PMC3140407
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Number of pages
- 11
- Grant note
- P50-CA58183 / NIH/NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Owens Foundation VA; US Department of Veterans Affairs Louisiana Cancer Research Consortium Voelcker Scholar Award CA34590; DK059389; CA125806 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA BCTR0601198 / Susan G. Komen Breast Cancer Foundation CA68485 / Core Facilities Vanderbilt Ingram Cancer Center
- Language
- English
- Date published
- 01/15/2011
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984420942802771
Metrics
4 Record Views