Abstract
IntroductionEndocrine 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.MethodsGene 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.ResultsBy 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, siCXCR7, as well as CCX733, a CXCR7 antagonist, specifically suppressed the proliferation of MCF7-LTED cells. siCXCR7 suppressed proteins associated with G1/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.ConclusionsThese data highlight CXCR7 as a potential therapeutic target warranting clinical investigation in endocrine-resistant BC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0447-1) contains supplementary material, which is available to authorized users.
Highlights
Endocrine therapies target oestrogenic stimulation of breast cancer (BC) growth, but resistance remains problematic
To identify clinically relevant molecular markers associated with resistance to Aromatase inhibitor (AI) that may be assessed in our in vitro models, we identified the intersection between genes that were significantly upregulated in MCF7 cells adapted to long-term oestrogen deprivation (LTED) [11] and genes predictive of a poor change in Ki67 in the clinical samples
This was of particular interest because previously we had shown by molecular profiling of AI-treated postmenopausal breast tumours that pretreatment expression of an inflammatory signature correlated with resistance to therapy [12]
Summary
Endocrine therapies target oestrogenic stimulation of breast cancer (BC) growth, but resistance remains problematic. Several endocrine therapies have been developed clinically to target this pathway, including aromatase inhibitors (AIs), which block the conversion of androgens to oestrogens; selective ER modulators such as tamoxifen, The elucidation of the molecular pathways governing resistance is crucial for the identification of biomarkers and novel therapeutic strategies. To answer these questions, we, like others, have developed in vitro models mimicking relapse on AIs. We have previously demonstrated that crosstalk between ER and type I and type II growth factor receptor tyrosine kinases, most notably. This suggests that alternative underlying molecular events remain to be identified
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