Cytokine receptor CXCR4 mediates estrogen-independent tumorigenesis, metastasis, and resistance to endocrine therapy in human breast cancer.

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 Res

journal_title

Cancer research

authors

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 CE

doi

10.1158/0008-5472.CAN-10-3185

subject

Has Abstract

pub_date

2011-01-15 00:00:00

pages

603-13

issue

2

eissn

0008-5472

issn

1538-7445

pii

0008-5472.CAN-10-3185

journal_volume

71

pub_type

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