title: Distinct patterns of dysregulated expression of enzymes involved in androgen synthesis and metabolism in metastatic prostate cancer tumors.
abstract: Androgen receptor (AR) signaling persists in castration-resistant prostate carcinomas (CRPC), because of several mechanisms that include increased AR expression and intratumoral androgen metabolism. We investigated the mechanisms underlying aberrant expression of transcripts involved in androgen metabolism in CRPC. We compared gene expression profiles and DNA copy number alteration (CNA) data from 29 normal prostate tissue samples, 127 primary prostate carcinomas (PCa), and 19 metastatic PCas. Steroidogenic enzyme transcripts were evaluated by quantitative reverse transcriptase PCR in PCa cell lines and circulating tumor cells (CTC) from CRPC patients. Metastatic PCas expressed higher transcript levels for AR and several steroidogenic enzymes, including SRD5A1, SRD5A3, and AKR1C3, whereas expression of SRD5A2, CYP3A4, CYP3A5, and CYP3A7 was decreased. This aberrant expression was rarely associated with CNAs. Instead, our data suggest distinct patterns of coordinated aberrant enzyme expression. Inhibition of AR activity by itself stimulated AKR1C3 expression. The aberrant expression of the steroidogenic enzyme transcripts was detected in CTCs from CRPC patients. In conclusion, our findings identify substantial interpatient heterogeneity and distinct patterns of dysregulated expression of enzymes involved in intratumoral androgen metabolism in PCa. These steroidogenic enzymes represent targets for complete suppression of systemic and intratumoral androgen levels, an objective that is supported by the clinical efficacy of the CYP17 inhibitor abiraterone. A comprehensive AR axis-targeting approach via simultaneous, frontline enzymatic blockade, and/or transcriptional repression of several steroidogenic enzymes, in combination with GnRH analogs and potent antiandrogens, would represent a powerful future strategy for PCa management.
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA. mitsiade@bcm.edu
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsiades
authors.forename: Clifford C
authors.initials: CC
authors.lastname: Sung
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Danila
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Eedunuri
authors.forename: Martin
authors.initials: M
authors.lastname: Fleisher
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000728:Androgens / Q000096:biosynthesis* / Q000378:metabolism; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D057225:Data Mining; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D009362:Neoplasm Metastasis; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D000728:Androgens; D012333:RNA, Messenger; D011944:Receptors, Androgen; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D051544:Cytochrome P-450 CYP3A; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase