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Introduction  Endocrine therapies target oestrogenic stimulation of breast cancer (BC) growth, but resistance remains problematic. Our aims in this study were (1) to identify genes most strongly associated with resistance to endocrine therapy by intersecting global gene transcription data from patients treated presurgically with the aromatase inhibitor anastrazole with those from MCF7 cells adapted to long-term oestrogen deprivation (LTED) (2) to assess the clinical value of selected genes in public clinical data sets and (3) to determine the impact of targeting these genes with novel agents.    Methods  Gene expression and Ki67 data were available from 69 postmenopausal women with oestrogen receptor–positive (ER+) early BC, at baseline and 2 weeks after anastrazole treatment, and from cell lines adapted to LTED. The functional consequences of target genes on proliferation, ER-mediated transcription and downstream cell signalling were assessed.    Results  By intersecting genes predictive of a poor change in Ki67 with those upregulated in LTED cells, we identified 32 genes strongly correlated with poor antiproliferative response that were associated with inflammation and/or immunity. In a panel of LTED cell lines, C-X-C chemokine receptor type 7 ( CXCR7 ) and  CXCR4  were upregulated compared to their wild types (wt), and  CXCR7 , but not  CXCR4 , was associated with reduced relapse-free survival in patients with ER+ BC. The CXCR4 small interfering RNA variant (siCXCR4) had no specific effect on the proliferation of wt-SUM44, wt-MCF7 and their LTED derivatives. In contrast, si CXCR7 , as well as CCX733, a CXCR7 antagonist, specifically suppressed the proliferation of MCF7-LTED cells. si CXCR7  suppressed proteins associated with G 1 /S transition and inhibited ER transactivation in MCF7-LTED, but not wt-MCF7, by impeding association between ER and proline-, glutamic acid– and leucine-rich protein 1, an ER coactivator.    Conclusions  These data highlight CXCR7 as a potential therapeutic target warranting clinical investigation in endocrine-resistant BC.    Electronic supplementary material  The online version of this article (doi:10.1186/s13058-014-0447-1) contains supplementary material, which is available to authorized users.

Identification of chemokine receptors as potential modulators of endocrine resistance in oestrogen receptor–positive breast cancers