title: The role of BPTF in melanoma progression and in response to BRAF-targeted therapy.
abstract: BACKGROUND
  Bromodomain PHD finger transcription factor (BPTF) plays an important role in chromatin remodeling, but its functional role in tumor progression is incompletely understood. Here we explore the oncogenic effects of BPTF in melanoma.
  
  
  METHODS
  The consequences of differential expression of BPTF were explored using shRNA-mediated knockdown in several melanoma cell lines. Immunoblotting was used to assess the expression of various proteins regulated by BPTF. The functional role of BPTF in melanoma progression was investigated using assays of colony formation, invasion, cell cycle, sensitivity to selective BRAF inhibitors, and in xenograft models of melanoma progression (n = 12 mice per group). The biomarker role of BPTF in melanoma progression was assessed using fluorescence in situ hybridization and immunohistochemical analyses. All statistical tests were two-sided.
  
  
  RESULTS
  shRNA-mediated BPTF silencing suppressed the proliferative capacity (by 65.5%) and metastatic potential (by 66.4%) of melanoma cells. Elevated BPTF copy number (mean ≥ 3) was observed in 28 of 77 (36.4%) melanomas. BPTF overexpression predicted poor survival in a cohort of 311 melanoma patients (distant metastasis-free survival P = .03, and disease-specific survival P = .008), and promoted resistance to BRAF inhibitors in melanoma cell lines. Metastatic melanoma tumors progressing on BRAF inhibitors contained low BPTF-expressing, apoptotic tumor cell subclones, indicating the continued presence of drug-responsive subclones within tumors demonstrating overall resistance to anti-BRAF agents.
  
  
  CONCLUSIONS
  These studies demonstrate multiple protumorigenic functions for BPTF and identify it as a novel target for anticancer therapy. They also suggest the combination of BPTF targeting with BRAF inhibitors as a novel therapeutic strategy for melanomas with mutant BRAF.
authors.affiliation: Center for Melanoma Research and Treatment (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, JRMIII, RWS, MKS), California Pacific Medical Center Research Institute, San Francisco, CA (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, LS, RD, JRMIII, RWS, MKS); Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, CA (SM); Life Technologies, Inc. Carlsbad, CA (PRB).
authors.forename: Altaf A
authors.initials: AA
authors.lastname: Dar
authors.affiliation: Center for Melanoma Research and Treatment (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, JRMIII, RWS, MKS), California Pacific Medical Center Research Institute, San Francisco, CA (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, LS, RD, JRMIII, RWS, MKS); Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, CA (SM); Life Technologies, Inc. Carlsbad, CA (PRB).
authors.forename: Mehdi
authors.initials: M
authors.lastname: Nosrati
authors.affiliation: Center for Melanoma Research and Treatment (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, JRMIII, RWS, MKS), California Pacific Medical Center Research Institute, San Francisco, CA (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, LS, RD, JRMIII, RWS, MKS); Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, CA (SM); Life Technologies, Inc. Carlsbad, CA (PRB).
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bezrookove
authors.affiliation: Center for Melanoma Research and Treatment (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, JRMIII, RWS, MKS), California Pacific Medical Center Research Institute, San Francisco, CA (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, LS, RD, JRMIII, RWS, MKS); Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, CA (SM); Life Technologies, Inc. Carlsbad, CA (PRB).
authors.forename: David
authors.initials: D
authors.lastname: de Semir
authors.affiliation: Center for Melanoma Research and Treatment (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, JRMIII, RWS, MKS), California Pacific Medical Center Research Institute, San Francisco, CA (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, LS, RD, JRMIII, RWS, MKS); Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, CA (SM); Life Technologies, Inc. Carlsbad, CA (PRB).
authors.forename: Shahana
authors.initials: S
authors.lastname: Majid
authors.affiliation: Center for Melanoma Research and Treatment (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, JRMIII, RWS, MKS), California Pacific Medical Center Research Institute, San Francisco, CA (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, LS, RD, JRMIII, RWS, MKS); Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, CA (SM); Life Technologies, Inc. Carlsbad, CA (PRB).
authors.forename: Suresh
authors.initials: S
authors.lastname: Thummala
authors.affiliation: Center for Melanoma Research and Treatment (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, JRMIII, RWS, MKS), California Pacific Medical Center Research Institute, San Francisco, CA (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, LS, RD, JRMIII, RWS, MKS); Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, CA (SM); Life Technologies, Inc. Carlsbad, CA (PRB).
authors.forename: Vera
authors.initials: V
authors.lastname: Sun
authors.affiliation: Center for Melanoma Research and Treatment (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, JRMIII, RWS, MKS), California Pacific Medical Center Research Institute, San Francisco, CA (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, LS, RD, JRMIII, RWS, MKS); Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, CA (SM); Life Technologies, Inc. Carlsbad, CA (PRB).
authors.forename: Schuyler
authors.initials: S
authors.lastname: Tong
authors.affiliation: Center for Melanoma Research and Treatment (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, JRMIII, RWS, MKS), California Pacific Medical Center Research Institute, San Francisco, CA (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, LS, RD, JRMIII, RWS, MKS); Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, CA (SM); Life Technologies, Inc. Carlsbad, CA (PRB).
authors.forename: Stanley P L
authors.initials: SP
authors.lastname: Leong
authors.affiliation: Center for Melanoma Research and Treatment (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, JRMIII, RWS, MKS), California Pacific Medical Center Research Institute, San Francisco, CA (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, LS, RD, JRMIII, RWS, MKS); Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, CA (SM); Life Technologies, Inc. Carlsbad, CA (PRB).
authors.forename: David
authors.initials: D
authors.lastname: Minor
authors.affiliation: Center for Melanoma Research and Treatment (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, JRMIII, RWS, MKS), California Pacific Medical Center Research Institute, San Francisco, CA (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, LS, RD, JRMIII, RWS, MKS); Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, CA (SM); Life Technologies, Inc. Carlsbad, CA (PRB).
authors.forename: Paul R
authors.initials: PR
authors.lastname: Billings
authors.affiliation: Center for Melanoma Research and Treatment (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, JRMIII, RWS, MKS), California Pacific Medical Center Research Institute, San Francisco, CA (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, LS, RD, JRMIII, RWS, MKS); Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, CA (SM); Life Technologies, Inc. Carlsbad, CA (PRB).
authors.forename: Liliana
authors.initials: L
authors.lastname: Soroceanu
authors.affiliation: Center for Melanoma Research and Treatment (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, JRMIII, RWS, MKS), California Pacific Medical Center Research Institute, San Francisco, CA (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, LS, RD, JRMIII, RWS, MKS); Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, CA (SM); Life Technologies, Inc. Carlsbad, CA (PRB).
authors.forename: Robert
authors.initials: R
authors.lastname: Debs
authors.affiliation: Center for Melanoma Research and Treatment (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, JRMIII, RWS, MKS), California Pacific Medical Center Research Institute, San Francisco, CA (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, LS, RD, JRMIII, RWS, MKS); Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, CA (SM); Life Technologies, Inc. Carlsbad, CA (PRB).
authors.forename: James R
authors.initials: JR
authors.lastname: Miller
authors.affiliation: Center for Melanoma Research and Treatment (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, JRMIII, RWS, MKS), California Pacific Medical Center Research Institute, San Francisco, CA (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, LS, RD, JRMIII, RWS, MKS); Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, CA (SM); Life Technologies, Inc. Carlsbad, CA (PRB).
authors.forename: Richard W
authors.initials: RW
authors.lastname: Sagebiel
authors.affiliation: Center for Melanoma Research and Treatment (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, JRMIII, RWS, MKS), California Pacific Medical Center Research Institute, San Francisco, CA (AAD, MN, VB, DdS, ST, VS, ST, SPLL, DM, LS, RD, JRMIII, RWS, MKS); Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, CA (SM); Life Technologies, Inc. Carlsbad, CA (PRB). kashani@cpmcri.org.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Kashani-Sabet
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D007093:Imidazoles / Q000494:pharmacology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007211:Indoles / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010091:Oximes / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D034961:Antigens, Nuclear; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007093:Imidazoles; D007211:Indoles; D009419:Nerve Tissue Proteins; D010091:Oximes; D048493:Proto-Oncogene Proteins B-raf; D013449:Sulfonamides; D014157:Transcription Factors; D000077484:Vemurafenib; C406238:fetal Alzheimer antigen; D000092468:Bromodomain Containing Proteins; C482120:Braf protein, mouse; C561627:dabrafenib