Cytokine receptor CXCR4 mediates estrogen-independent tumorigenesis, metastasis, and resistance to endocrine therapy in human breast cancer.
Cytokine receptor CXCR4 mediates estrogen-independent tumorigenesis, metastasis, and resistance to endocrine therapy in human breast cancer.
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DOI：
10.1158/0008-5472.can-10-3185
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发表时间：
2011-01-15
期刊：
影响因子：
11.2
通讯作者：
Burow ME
中科院分区：
文献类型：
--
作者：
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;Fuqua SA;Nephew KP;Dent P;Worthylake RA;Curiel TJ;Hung MC;Richmond A;Burow ME
雌激素不依赖性和进展为转移表型是乳腺癌患者治疗抵抗和死亡率的标志。转移与通过SDF-1-CXCR 4轴的趋化因子信号传导相关。因此，乳腺癌患者中雌激素非依赖性和内分泌治疗抗性的发展可能是由SDF-1-CXCR 4信号传导驱动的。在这里，我们报告说，CXCR 4过表达确实与预后不良和降低患者生存率，无论雌激素受体（ER）的状态。在转移性差的MCF-7细胞中，CXCR 4的组成性激活导致肿瘤生长和转移增强，这可以通过CXCR 4抑制来逆转。MCF-7细胞中CXCR 4过表达促进了体内雌激素非依赖性，而外源性SDF-1治疗否定了用抗雌激素ICI 182，780治疗对CXCR 4介导的肿瘤生长的抑制作用。CXCR 4过表达的影响与SDF-1介导的下游信号转导激活（通过ERK 1/2和p38 MAPK（促分裂原活化蛋白激酶））以及ER介导的基因表达增强相关。总之，这些结果表明，增强的CXCR 4信号足以通过增加的MAPK信号将ER阳性乳腺癌驱动为转移性和内分泌治疗抗性表型。我们的研究结果突出了CXCR 4信号传导作为治疗ER阳性、雌激素非依赖性乳腺癌的合理治疗靶点，需要改善临床管理。
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.