title: The Estrogen Receptor Cofactor SPEN Functions as a Tumor Suppressor and Candidate Biomarker of Drug Responsiveness in Hormone-Dependent Breast Cancers.
abstract: The treatment of breast cancer has benefitted tremendously from the generation of estrogen receptor-α (ERα)-targeted therapies, but disease relapse continues to pose a challenge due to intrinsic or acquired drug resistance. In an effort to delineate potential predictive biomarkers of therapy responsiveness, multiple groups have identified several uncharacterized cofactors and interacting partners of ERα, including Split Ends (SPEN), a transcriptional corepressor. Here, we demonstrate a role for SPEN in ERα-expressing breast cancers. SPEN nonsense mutations were detectable in the ERα-expressing breast cancer cell line T47D and corresponded to undetectable protein levels. Further analysis of 101 primary breast tumors revealed that 23% displayed loss of heterozygosity at the SPEN locus and that 3% to 4% harbored somatically acquired mutations. A combination of in vitro and in vivo functional assays with microarray-based pathway analyses showed that SPEN functions as a tumor suppressor to regulate cell proliferation, tumor growth, and survival. We also found that SPEN binds ERα in a ligand-independent manner and negatively regulates the transcription of ERα targets. Moreover, we demonstrate that SPEN overexpression sensitizes hormone receptor-positive breast cancer cells to the apoptotic effects of tamoxifen, but has no effect on responsiveness to fulvestrant. Consistent with these findings, two independent datasets revealed that high SPEN protein and RNA expression in ERα-positive breast tumors predicted favorable outcome in patients treated with tamoxifen alone. Together, our data suggest that SPEN is a novel tumor-suppressor gene that may be clinically useful as a predictive biomarker of tamoxifen response in ERα-positive breast cancers.
authors: Department of Surgery and Oncology, McGill University, Montréal, Québec, Canada. Department of Oncology and Surgery, Lady Davis Institute for Medical Research, Montréal, Québec, Canada.
authors: Stéphanie
authors: S
authors: Légaré
authors: Department of Oncology and Surgery, Lady Davis Institute for Medical Research, Montréal, Québec, Canada.
authors: Luca
authors: L
authors: Cavallone
authors: Department of Oncology and Surgery, Lady Davis Institute for Medical Research, Montréal, Québec, Canada.
authors: Aline
authors: A
authors: Mamo
authors: Department of Oncology and Surgery, Lady Davis Institute for Medical Research, Montréal, Québec, Canada.
authors: Catherine
authors: C
authors: Chabot
authors: Department of Surgery and Oncology, McGill University, Montréal, Québec, Canada. Department of Oncology and Surgery, Lady Davis Institute for Medical Research, Montréal, Québec, Canada.
authors: Isabelle
authors: I
authors: Sirois
authors: Department of Pathology, University of Calgary, Calgary, Alberta, Canada.
authors: Anthony
authors: A
authors: Magliocco
authors: Department of Pathology, University of Calgary, Calgary, Alberta, Canada.
authors: Alexander
authors: A
authors: Klimowicz
authors: Department of Human Genetics, McGill University and The Research Institute of the McGill University Health Centre, Montréal, Québec, Canada. Department of Medicine, McGill University and The Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.
authors: Patricia N
authors: PN
authors: Tonin
authors: Department of Oncology and Surgery, Lady Davis Institute for Medical Research, Montréal, Québec, Canada.
authors: Marguerite
authors: M
authors: Buchanan
authors: Department of Surgery and Oncology, McGill University, Montréal, Québec, Canada. Department of Oncology and Surgery, Lady Davis Institute for Medical Research, Montréal, Québec, Canada.
authors: Dana
authors: D
authors: Keilty
authors: Department of Surgery and Oncology, McGill University, Montréal, Québec, Canada. Department of Oncology and Surgery, Lady Davis Institute for Medical Research, Montréal, Québec, Canada.
authors: Saima
authors: S
authors: Hassan
authors: Institut de recherche en immunologie et cancérologie, IRIC, Montréal, Québec, Canada.
authors: David
authors: D
authors: Laperrière
authors: Institut de recherche en immunologie et cancérologie, IRIC, Montréal, Québec, Canada. Department de Biochimie, Université de Montréal, Montréal, Québec, Canada.
authors: Sylvie
authors: S
authors: Mader
authors: Department of Pathology, Jewish General Hospital, Montréal, Quebec, Canada.
authors: Olga
authors: O
authors: Aleynikova
authors: Department of Surgery and Oncology, McGill University, Montréal, Québec, Canada. Department of Oncology and Surgery, Lady Davis Institute for Medical Research, Montréal, Québec, Canada. mark.basik@mcgill.ca.
authors: Mark
authors: M
authors: Basik
mesh_terms: D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D016923:Cell Death; D045744:Cell Line, Tumor; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen; C476510:SPEN protein, human; D025521:Tumor Suppressor Proteins