Cytokine receptor CXCR4 mediates estrogen-independent tumorigenesis, metastasis, and resistance to endocrine therapy in human breast cancer.
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.
Department of Medicine, Section of Hematology and Medical Oncology, Center for Bioenvironmental Research, Tulane University Health Sciences Center, New Orleans, Louisiana 70112, USA.
Lyndsay V
LV
Rhodes
Sarah P
SP
Short
Nicole F
NF
Neel
Virgilio A
VA
Salvo
Yun
Y
Zhu
Steven
S
Elliott
Yongkun
Y
Wei
Dihua
D
Yu
Menghong
M
Sun
Shannon E
SE
Muir
Juan P
JP
Fonseca
Melyssa R
MR
Bratton
Chris
C
Segar
Syreeta L
SL
Tilghman
Tammy
T
Sobolik-Delmaire
Linda W
LW
Horton
Snjezana
S
Zaja-Milatovic
Bridgette M
BM
Collins-Burow
Scott
S
Wadsworth
Barbara S
BS
Beckman
Charles E
CE
Wood
Suzanne A
SA
Fuqua
Kenneth P
KP
Nephew
Paul
P
Dent
Rebecca A
RA
Worthylake
Tyler J
TJ
Curiel
Mien-Chie
MC
Hung
Ann
A
Richmond
Matthew E
ME
Burow
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D018931:Antineoplastic Agents, Hormonal; C527276:CXCR4 protein, human; D004965:Estrogen Antagonists; D019718:Receptors, CXCR4; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D004958:Estradiol