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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Rhodes LV,Short SP,Neel NF,Salvo VA,Zhu Y,Elliott S,Wei Y,Yu D,Sun M,Muir SE,Fonseca JP,Bratton MR,Segar C,Tilghman SL,Sobolik-Delmaire T,Horton LW,Zaja-Milatovic S,Collins-Burow BM,Wadsworth S,Beckman BS,Wood CEdoi
10.1158/0008-5472.CAN-10-3185subject
Has Abstractpub_date
2011-01-15 00:00:00pages
603-13issue
2eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-10-3185journal_volume
71pub_type
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