title: Loss of TGFβ Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance.
abstract: One third of the patients with estrogen receptor α (ERα)-positive breast cancer who are treated with the antiestrogen tamoxifen will either not respond to initial therapy or will develop drug resistance. Endocrine response involves crosstalk between ERα and TGFβ signaling, such that tamoxifen nonresponsiveness or resistance in breast cancer might involve aberrant TGFβ signaling. In this study, we analyzed TGFβ receptor type 2 (TGFBR2) expression and correlated it with ERα status and phosphorylation in a cohort of 564 patients who had been randomized to tamoxifen or no-adjuvant treatment for invasive breast carcinoma. We also evaluated an additional four independent genetic datasets in invasive breast cancer. In all the cohorts we analyzed, we documented an association of low TGFBR2 protein and mRNA expression with tamoxifen resistance. Functional investigations confirmed that cell cycle or apoptosis responses to estrogen or tamoxifen in ERα-positive breast cancer cells were impaired by TGFBR2 silencing, as was ERα phosphorylation, tamoxifen-induced transcriptional activation of TGFβ, and upregulation of the multidrug resistance protein ABCG2. Acquisition of low TGFBR2 expression as a contributing factor to endocrine resistance was validated prospectively in a tamoxifen-resistant cell line generated by long-term drug treatment. Collectively, our results established a central contribution of TGFβ signaling in endocrine resistance in breast cancer and offered evidence that TGFBR2 can serve as an independent biomarker to predict treatment outcomes in ERα-positive forms of this disease.
authors.affiliation: Sahlgrenska Cancer Center, Gothenburg University, Gothenburg, Sweden.
authors.forename: Susann
authors.initials: S
authors.lastname: Busch
authors.affiliation: Applied Bioinformatics of Cancer, University of Edinburgh, Cancer Research UK Centre, United Kingdom.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Sims
authors.affiliation: Department of Clinical and Experimental Medicine, Institution of Surgery and Clinical Oncology, Linköpings Universitet, Linköping, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Stål
authors.affiliation: Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Mårten
authors.initials: M
authors.lastname: Fernö
authors.affiliation: Sahlgrenska Cancer Center, Gothenburg University, Gothenburg, Sweden. Molecular Pathology, Breakthrough Breast Cancer Research Unit, University of Manchester, United Kingdom. Goran.Landberg@gu.se.
authors.forename: Göran
authors.initials: G
authors.lastname: Landberg
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D049109:Cell Proliferation; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D004967:Estrogens / Q000502:physiology*; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D016016:Proportional Hazards Models; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D020239:Receptor Cross-Talk; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D018931:Antineoplastic Agents, Hormonal; D004967:Estrogens; D009363:Neoplasm Proteins; D018125:Receptors, Transforming Growth Factor beta; D013629:Tamoxifen; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II