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¹ Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy² Molecular Cancer Genetics, Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy³ Departments of Medical Oncology⁴ Surgery⁵ Pathology⁶ Scientific Direction, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy

(Correspondence should be addressed to M G Daidone, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy; Email: mariagrazia.daidone{at}istitutotumori.mi.it)

This study aimed to define a gene expression profile associated with response to anti-estrogen treatment in estrogen receptor (ER)-positive breast cancer from elderly patients and to identify possible candidate genes associated with resistance by detecting those modulated by treatment. Using cDNA microarrays containing 16 702 unique clones, 21 pre-treatment and 11 paired post-treatment samples collected in a neo-adjuvant toremifene trial on elderly patients with operable and locally advanced ER-positive breast cancer were profiled. Gene expression profiles generated from pre-treatment samples were correlated with treatment-induced tumor shrinkage and compared with those obtained from post-treatment paired samples to define genes differentially modulated following anti-estrogen treatment. Correlation analysis on 21 pre-treatment samples highlighted 53 genes significantly related to treatment response (P<0.001). Genes involved in cell cycle and proliferation were more frequently upregulated in responders compared with non-responders. Class comparison analysis identified 101 genes significantly modulated independently of treatment response; 82 genes were modulated in non-responders, whereas only 8 genes were differently expressed after treatment in responders. Gene expression profiles appear to be more frequently modulated by anti-estrogen treatment in non-responding patients and may harbor interesting genes possibly involved in anti-estrogen resistance, including clusterin, MAPK6, and MMP2. This concept was corroborated by in vitro studies showing that silencing of CLU restored toremifene sensitivity in the ER anti-estrogen-resistant breast cancer cell line T47D. Integration between neo-adjuvant therapy and transcriptional profiling has therefore the potential to identify therapeutic targets to be challenged for overcoming treatment resistance.