title: Androgen Receptor Tumor Suppressor Function Is Mediated by Recruitment of Retinoblastoma Protein.
abstract: Although well characterized as a transcriptional activator that drives prostate cancer (PCa) growth, androgen receptor (AR) can function as a transcriptional repressor, and high-level androgens can suppress PCa proliferation. The molecular basis for this repression activity remains to be determined. Genes required for DNA replication are highly enriched among androgen-repressed genes, and AR is recruited to the majority of these genes, where it rapidly represses their transcription. This activity is enhanced in PCa cells expressing high AR levels and is mediated by recruitment of hypophosphorylated retinoblastoma protein (Rb). Significantly, AR also indirectly increases the expression of DNA replication genes through stimulatory effects on other metabolic genes with subsequent CDK activation and Rb hyperphosphorylation. In castration-resistant PCa cells, which are dependent on high-level AR expression, this anti-proliferative repression function might be exploited through treatment with androgen in combination with agents that suppress AR-driven metabolic functions or cell cycle progression.
authors.affiliation: Center for Personalized Cancer Therapy, University of Massachusetts, Boston, Boston, MA 02125, USA; Hematology-Oncology Division and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Shuai
authors.initials: S
authors.lastname: Gao
authors.affiliation: Hematology-Oncology Division and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of Orthopedics, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Ontario Cancer Institute, Princess Margaret Cancer Center/University Health Network, Toronto, ON M5G1L7, Canada.
authors.forename: Housheng Hansen
authors.initials: HH
authors.lastname: He
authors.affiliation: Center for Personalized Cancer Therapy, University of Massachusetts, Boston, Boston, MA 02125, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Han
authors.affiliation: Center for Personalized Cancer Therapy, University of Massachusetts, Boston, Boston, MA 02125, USA.
authors.forename: Wanting
authors.initials: W
authors.lastname: Han
authors.affiliation: Center for Personalized Cancer Therapy, University of Massachusetts, Boston, Boston, MA 02125, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Avery
authors.affiliation: Center for Personalized Cancer Therapy, University of Massachusetts, Boston, Boston, MA 02125, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Macoska
authors.affiliation: Department of Urology, Tongji Hospital, Wuhan, Hubei 430030, China.
authors.forename: Xiaming
authors.initials: X
authors.lastname: Liu
authors.affiliation: Hematology-Oncology Division and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Sen
authors.initials: S
authors.lastname: Chen
authors.affiliation: Hematology-Oncology Division and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Fen
authors.initials: F
authors.lastname: Ma
authors.affiliation: Hematology-Oncology Division and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. Electronic address: schen@bidmc.harvard.edu.
authors.forename: Shaoyong
authors.initials: S
authors.lastname: Chen
authors.affiliation: Hematology-Oncology Division and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. Electronic address: sbalk@bidmc.harvard.edu.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
authors.affiliation: Center for Personalized Cancer Therapy, University of Massachusetts, Boston, Boston, MA 02125, USA; Hematology-Oncology Division and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. Electronic address: changmeng.cai@umb.edu.
authors.forename: Changmeng
authors.initials: C
authors.lastname: Cai
mesh_terms: D000728:Androgens / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004261:DNA Replication / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant; D011944:Receptors, Androgen / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C410798:AR protein, human; D000728:Androgens; D011944:Receptors, Androgen; D016160:Retinoblastoma Protein; D018844:Cyclin-Dependent Kinases
keywords: AR; DNA damage repair; DNA replication; E2F1; Rb; Retinoblastoma protein; androgen deprivation therapy; androgen receptor; metabolism; prostate cancer; transcriptional repression