title: Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response.
abstract: Novel therapies for men with castration-resistant prostate cancer (CRPC) are needed, particularly for cancers not driven by androgen receptor (AR) activation.
  
  
  
  To identify molecular subgroups of PC bone metastases of relevance for therapy.
  
  
  
  Fresh-frozen bone metastasis samples from men with CRPC (n=40), treatment-naïve PC (n=8), or other malignancies (n=12) were characterized using whole-genome expression profiling, multivariate principal component analysis (PCA), and functional enrichment analysis. Expression profiles were verified by reverse transcription-polymerase chain reaction (RT-PCR) in an extended set of bone metastases (n=77) and compared to levels in malignant and adjacent benign prostate tissue from patients with localized disease (n=12). Selected proteins were evaluated using immunohistochemistry. A cohort of PC patients (n=284) diagnosed at transurethral resection with long follow-up was used for prognostic evaluation.
  
  
  
  The majority of CRPC bone metastases (80%) was defined as AR-driven based on PCA analysis and high expression of the AR, AR co-regulators (FOXA1, HOXB13), and AR-regulated genes (KLK2, KLK3, NKX3.1, STEAP2, TMPRSS2); 20% were non-AR-driven. Functional enrichment analysis indicated high metabolic activity and low immune responses in AR-driven metastases. Accordingly, infiltration of CD3+and CD68+cells was lower in AR-driven than in non-AR-driven metastases, and tumor cell HLA class I ABC immunoreactivity was inversely correlated with nuclear AR immunoreactivity. RT-PCR analysis showed low MHC class I expression (HLA-A, TAP1, and PSMB9 mRNA) in PC bone metastases compared to benign and malignant prostate tissue and bone metastases of other origins. In primary PC, low HLA class I ABC immunoreactivity was associated with high Gleason score, bone metastasis, and short cancer-specific survival. Limitations include the limited number of patients studied and the single metastasis sample studied per patient.
  
  
  
  Most CRPC bone metastases show high AR and metabolic activities and low immune responses. A subgroup instead shows low AR and metabolic activities, but high immune responses. Targeted therapy for these groups should be explored.
  
  
  
  We studied heterogeneities at a molecular level in bone metastasis samples obtained from men with castration-resistant prostate cancer. We found differences of possible importance for therapy selection in individual patients.
authors: Department of Medical Biosciences, Pathology, Umea University, Umea, Sweden.
authors: Erik Bovinder
authors: EB
authors: Ylitalo
authors: Department of Medical Biosciences, Pathology, Umea University, Umea, Sweden.
authors: Elin
authors: E
authors: Thysell
authors: Department of Medical Biosciences, Pathology, Umea University, Umea, Sweden.
authors: Emma
authors: E
authors: Jernberg
authors: Department of Medical Biosciences, Pathology, Umea University, Umea, Sweden.
authors: Marie
authors: M
authors: Lundholm
authors: Department of Surgery and Perioperative Sciences, Orthopedics, Umea University, Umea, Sweden.
authors: Sead
authors: S
authors: Crnalic
authors: Section of Urology, Department of Surgical Science, Karolinska Institutet, Stockholm, Sweden.
authors: Lars
authors: L
authors: Egevad
authors: Department of Surgery and Perioperative Sciences, Urology & Andrology, Umea University, Umea, Sweden.
authors: Pär
authors: P
authors: Stattin
authors: Department of Radiation Sciences, Oncology, Umea University, Umea, Sweden.
authors: Anders
authors: A
authors: Widmark
authors: Department of Medical Biosciences, Pathology, Umea University, Umea, Sweden.
authors: Anders
authors: A
authors: Bergh
authors: Department of Medical Biosciences, Pathology, Umea University, Umea, Sweden. Electronic address: pernilla.wikstrom@umu.se.
authors: Pernilla
authors: P
authors: Wikström
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2 / Q000235:genetics / Q000276:immunology; D000368:Aged; D000369:Aged, 80 and over; D001859:Bone Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000556:secondary; D016022:Case-Control Studies; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007610:Kallikreins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000235:genetics; D010088:Oxidoreductases / Q000235:genetics; D025341:Principal Component Analysis; D017430:Prostate-Specific Antigen / Q000235:genetics; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: C410798:AR protein, human; D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; C496499:FOXA1 protein, human; D015234:HLA-A Antigens; C484414:HOXB13 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D018398:Homeodomain Proteins; D008565:Membrane Proteins; C491178:NKX3-1 protein, human; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D011944:Receptors, Androgen; C073119:TAP1 protein, human; D014157:Transcription Factors; C071313:LMP-2 protein; D010088:Oxidoreductases; C467741:STEAP2 protein, human; C000595667:KLK2 protein, human; C549870:KLK3 protein, human; D007610:Kallikreins; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human; D017430:Prostate-Specific Antigen; D003546:Cysteine Endopeptidases
keywords: Bone metastasis; Castration-resistance; Immune response; Metabolism; Prostate cancer