title: Androgen receptor splice variants determine taxane sensitivity in prostate cancer.
abstract: Prostate cancer growth depends on androgen receptor signaling. Androgen ablation therapy induces expression of constitutively active androgen receptor splice variants that drive disease progression. Taxanes are a standard of care therapy in castration-resistant prostate cancer (CRPC); however, mechanisms underlying the clinical activity of taxanes are poorly understood. Recent work suggests that the microtubule network of prostate cells is critical for androgen receptor nuclear translocation and activity. In this study, we used a set of androgen receptor deletion mutants to identify the microtubule-binding domain of the androgen receptor, which encompasses the DNA binding domain plus hinge region. We report that two clinically relevant androgen receptor splice variants, ARv567 and ARv7, differentially associate with microtubules and dynein motor protein, thereby resulting in differential taxane sensitivity in vitro and in vivo. ARv7, which lacks the hinge region, did not co-sediment with microtubules or coprecipitate with dynein motor protein, unlike ARv567. Mechanistic investigations revealed that the nuclear accumulation and transcriptional activity of ARv7 was unaffected by taxane treatment. In contrast, the microtubule-interacting splice variant ARv567 was sensitive to taxane-induced microtubule stabilization. In ARv567-expressing LuCap86.2 tumor xenografts, docetaxel treatment was highly efficacious, whereas ARv7-expressing LuCap23.1 tumor xenografts displayed docetaxel resistance. Our results suggest that androgen receptor variants that accumulate in CRPC cells utilize distinct pathways of nuclear import that affect the antitumor efficacy of taxanes, suggesting a mechanistic rationale to customize treatments for patients with CRPC, which might improve outcomes.
authors.affiliation: Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, New York 10065-4896, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Thadani-Mulero
authors.affiliation: Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, New York 10065-4896, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Portella
authors.affiliation: Department of Urology, University of Washington, Seattle, WA, 98195 USA.
authors.forename: Shihua
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, New York 10065-4896, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Sung
authors.affiliation: Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, New York 10065-4896, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Matov
authors.affiliation: Department of Urology, University of Washington, Seattle, WA, 98195 USA.|Research Service, Puget Sound VA Health Care System, Seattle, WA, 98116, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.affiliation: Department of Urology, University of Washington, Seattle, WA, 98195 USA.|Research Service, Puget Sound VA Health Care System, Seattle, WA, 98116, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Corey
authors.affiliation: Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, New York 10065-4896, USA.|Weill Cornell Cancer Center, New York, New York 10065-4896, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Nanus
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington 98195, USA.|GRECC Seattle VAMC, Seattle, WA 98116, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Plymate
authors.affiliation: Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, New York 10065-4896, USA.|Weill Cornell Cancer Center, New York, New York 10065-4896, USA.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Giannakakou
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004195:Disease Models, Animal; D000077143:Docetaxel; D000072159:Dynactin Complex; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics; D008870:Microtubules / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D012326:RNA Splicing; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D043823:Taxoids / Q000494:pharmacology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D020033:Protein Isoforms; D011944:Receptors, Androgen; D043823:Taxoids; D000077143:Docetaxel