title: Gene expression alterations associated with outcome in aromatase inhibitor-treated ER+ early-stage breast cancer patients.
abstract: Aromatase inhibitors (AI), either alone or together with chemotherapy, have become the standard adjuvant treatment for postmenopausal, estrogen receptor-positive (ER+) breast cancer. Although AIs improve overall survival, resistance is still a major clinical problem, thus additional biomarkers predictive of outcome of ER+ breast cancer patients treated with AIs are needed. Global gene expression analysis was performed on ER+ primary breast cancers from patients treated with adjuvant AI monotherapy; half experienced recurrence (median follow-up 6.7 years). Gene expression alterations were validated by qRT-PCR, and functional studies evaluating the effect of siRNA-mediated gene knockdown on cell growth were performed. Twenty-six genes, including TFF3, DACH1, RGS5, and GHR, were shown to exhibit altered expression in tumors from patients with recurrence versus non-recurrent (fold change ≥1.5, p < 0.05), and the gene expression alterations were confirmed using qRT-PCR. Ten of these 26 genes could be linked in a network associated with cellular proliferation, growth, and development. TFF3, which encodes for trefoil factor 3 and is an estrogen-responsive oncogene shown to play a functional role in tamoxifen resistance and metastasis of ER+ breast cancer, was also shown to be upregulated in an AI-resistant cell line model, and reduction of TFF3 levels using TFF3-specific siRNAs decreased the growth of both the AI-resistant and -sensitive parental cell lines. Moreover, overexpression of TFF3 in parental AI-sensitive MCF-7/S0.5 cells resulted in reduced sensitivity to the AI exemestane, whereas TFF3 overexpression had no effect on growth in the absence of exemestane, indicating that TFF3 mediates growth and survival signals that abrogate the growth inhibitory effect of exemestane. We identified a panel of 26 genes exhibiting altered expression associated with disease recurrence in patients treated with adjuvant AI monotherapy, including TFF3, which was shown to exhibit a growth- and survival-promoting effect in the context of AI treatment.
authors.affiliation: Institute of Molecular Medicine, Department of Cancer and Inflammation Research, University of Southern Denmark, J. B. Winslowsvej 25, 5000, Odense, Denmark.
authors.forename: Karina G
authors.initials: KG
authors.lastname: Thomsen
authors.affiliation: Institute of Molecular Medicine, Department of Cancer and Inflammation Research, University of Southern Denmark, J. B. Winslowsvej 25, 5000, Odense, Denmark.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Lyng
authors.affiliation: Institute of Molecular Medicine, Department of Cancer and Inflammation Research, University of Southern Denmark, J. B. Winslowsvej 25, 5000, Odense, Denmark.
authors.forename: Daniel
authors.initials: D
authors.lastname: Elias
authors.affiliation: Institute of Molecular Medicine, Department of Cancer and Inflammation Research, University of Southern Denmark, J. B. Winslowsvej 25, 5000, Odense, Denmark.
authors.forename: Henriette
authors.initials: H
authors.lastname: Vever
authors.affiliation: Department of Oncology, Copenhagen University Hospital, Rigshospitalet, 2100, Copenhagen, Denmark.
authors.forename: Ann S
authors.initials: AS
authors.lastname: Knoop
authors.affiliation: Breast Cancer Group, Cell Death and Metabolism, Danish Cancer Society Research Center, 2100, Copenhagen, Denmark.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Lykkesfeldt
authors.affiliation: Department of Pathology, Slagelse Hospital, 4200, Slagelse, Denmark.
authors.forename: Anne-Vibeke
authors.initials: AV
authors.lastname: Lænkholm
authors.affiliation: Institute of Molecular Medicine, Department of Cancer and Inflammation Research, University of Southern Denmark, J. B. Winslowsvej 25, 5000, Odense, Denmark. hditzel@health.sdu.dk.|Department of Oncology, Odense University Hospital, 5000, Odense, Denmark. hditzel@health.sdu.dk.
authors.forename: Henrik J
authors.initials: HJ
authors.lastname: Ditzel
mesh_terms: D000368:Aged; D000730:Androstadienes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D009570:Nitriles / Q000627:therapeutic use*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D012189:Retrospective Studies; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D000071165:Trefoil Factor-3; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; C486747:DACH1 protein, human; D005136:Eye Proteins; D009570:Nitriles; D010455:Peptides; D020710:RGS Proteins; C491349:RGS5 protein, human; D011960:Receptors, Estrogen; C082495:TFF3 protein, human; D014157:Transcription Factors; D000071165:Trefoil Factor-3; D014230:Triazoles; D000077289:Letrozole; C056516:exemestane
keywords: Aromatase inhibitors; Biomarkers; Breast cancer; Endocrine resistance; Estrogen receptor; TFF3