A Novel Mechanism for Control of Androgen Receptor Levels in HRPC

HRPC 中雄激素受体水平控制的新机制

• 批准号: 8447576
• 负责人: ANNE W. HAMBURGER
• 金额: $ 26.33万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8447576
• 关键词: 3' Untranslated Regions; Affect; Androgen Receptor; Androgens; Animal Model; Binding; Biological Markers; Biology; Cancer Cell Growth; Castration; Clinical; Complex; Data; Disease; Event; Gene Proteins; Gene Targeting; Genetic Translation; Grant; Growth; Heregulin; Hormones; In Vitro; Indium; Knockout Mice; Laboratories; Ligands; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; Messenger RNA; Mutation; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Phosphorylation; Physiological; Play; Proteins; Publishing; RNA-Binding Proteins; Receptor Signaling; Regulation; Resistance; Role; Signal Transduction; Somatotropin; Testosterone; Therapeutic; Time; Tyrosine Kinase Inhibitor; United States; Work; base; cancer therapy; castration resistant prostate cancer; cell growth; clinical efficacy; design; hormone refractory prostate cancer; in vivo; in vivo Model; inhibitor/antagonist; kinase inhibitor; mRNA Stability; men; mortality; mouse model; novel; novel strategies; novel therapeutics; prostate cancer cell; public health relevance; receptor; receptor function; research study; response; tumor

DESCRIPTION (provided by applicant): The androgen receptor (AR) is central to the initiation and growth of prostate cancer and to the therapeutic response to hormones. Although the expression and activity of AR is controlled by AR coregulators, the manipulation of endogenous AR corepressors to downregulate AR levels has not been exploited therapeutically. We have demonstrated that EBP1, a protein isolated in our laboratory by its ability to bind ErbB3, is an AR corepressor that suppresses protein levels of AR and AR target genes and inhibits growth of prostate cancer cells. The ability of EBP1 to repress AR function can be regulated by the ErbB3/4 ligand heregulin (HRG) an important modulator of prostate cancer cell growth. Recent work from independent laboratories has shown that activation of the ErbB2/3 heterodimer by HRG can destabilize endogenous AR mRNA. We hypothesize that EBP1 mediates the effects of HRG by binding to and destabilizing AR mRNA in an HRG-inducible manner. Further, we postulate that the clinical efficacy of ErbB tyrosine kinase inhibitors (TKIs) has been disappointing because inhibition of ErbB activity results in abrogation of HRG-induced AR destabilization. Our preliminary and published data indicate that EBP1 modulates the growth of prostate cancer cells in response to HRG to TKIs. This grant will delineate the ability of EBP1 to affect the sensitivity of prostate cancer cells to TKIs and the role that EBP1-induced destabilization of AR plays in this response. We hypothesize that EBP1 may be a novel biomarker that can be used to identify patients that may benefit from ErbB directed therapies. The purpose of Specific Aim 1 is to elucidate the mechanism of the destabilization of AR mRNA by EBP1. These studies will a) determine the regions of interaction between EBP1 and AR mRNA in vivo and their functional significance b) determine the role of EBP1 in mediating HRG's destabilization of AR mRNA c) determine the regulation of EBP1-AR mRNA interactions in a physiological relevant setting using the Ebp1 knock out mouse model. The purpose of Specific Aim II is to determine if EBP1 status affects the ability of prostate cancer cells to respond to TKIs. We will use both in vitro and in vivo models to determine if manipulation of EBP1 levels or mutation of EBP1 can alter cellular response to TKIs. We will examine if the observed effects are regulated via EBP1-induced AR destabilization.

描述（由申请人提供）：雄激素受体（AR）对于前列腺癌的发生和生长以及对激素的治疗​​反应至关重要。尽管AR的表达和活性是由AR辅调节子控制的，但操纵内源性AR辅阻遏物来下调AR水平尚未在治疗上得到利用。我们已经证明，EBP1（我们实验室通过其结合 ErbB3 的能力分离出的一种蛋白质）是一种 AR 辅阻遏物，可抑制 AR 和 AR 靶基因的蛋白质水平并抑制前列腺癌细胞的生长。 EBP1 抑制 AR 功能的能力可以通过 ErbB3/4 配体调蛋白 (HRG) 进行调节，HRG 是前列腺癌细胞生长的重要调节剂。独立实验室最近的工作表明，HRG 激活 ErbB2/3 异二聚体可以破坏内源 AR mRNA 的稳定性。我们假设 EBP1 通过以 HRG 诱导的方式结合 AR mRNA 并使其不稳定来介导 HRG 的作用。此外，我们假设 ErbB 酪氨酸激酶抑制剂 (TKI) 的临床疗效令人失望，因为抑制 ErbB 活性会导致 HRG 诱导的 AR 不稳定的消除。我们的初步和已发表的数据表明，EBP1 可响应 HRG 和 TKI 调节前列腺癌细胞的生长。这笔资助将描述 EBP1 影响前列腺癌细胞对 TKI 敏感性的能力，以及 EBP1 诱导的 AR 不稳定在这种反应中所起的作用。我们假设 EBP1 可能是一种新型生物标志物，可用于识别可能受益于 ErbB 定向疗法的患者。具体目标1的目的是阐明EBP1使AR mRNA不稳定的机制。这些研究将 a) 确定 EBP1 和 AR mRNA 体内相互作用的区域及其功能意义 b) 确定 EBP1 在介导 HRG 使 AR mRNA 不稳定中的作用 c) 使用 Ebp1 敲除小鼠模型确定生理相关环境中 EBP1-AR mRNA 相互作用的调节。 Specific Aim II 的目的是确定 EBP1 状态是否影响前列腺癌细胞对 TKI 的反应能力。我们将使用体外和体内模型来确定 EBP1 水平的操纵或 EBP1 突变是否可以改变细胞对 TKI 的反应。我们将检查观察到的效应是否是通过 EBP1 诱导的 AR 不稳定来调节的。

项目成果

EBP1 inhibits translation of androgen receptor mRNA in castration resistant prostate cancer cells.

• 发表时间: 2011-10
• 期刊: Anticancer research
• 影响因子: 2
• 作者: Hua Zhou;Yuexing Zhang;A. Hamburger

The ErbB3-binding protein EBP1 modulates lapatinib sensitivity in prostate cancer cells.

• DOI: 10.1007/s11010-015-2409-z
• 发表时间: 2015-07
• 期刊: MOLECULAR AND CELLULAR BIOCHEMISTRY
• 影响因子: 4.3
• 作者: Awasthi, Smita;Ezelle, Heather;Hassel, Bret A.;Hamburger, Anne W.
• 通讯作者: Hamburger, Anne W.

Functional cyclic AMP response element in the breast cancer resistance protein (BCRP/ABCG2) promoter modulates epidermal growth factor receptor pathway- or androgen withdrawal-mediated BCRP/ABCG2 transcription in human cancer cells.

• DOI: 10.1016/j.bbagrm.2015.01.003
• 发表时间: 2015-03
• 期刊: BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
• 影响因子: 4.7
• 作者: Xie, Yi;Nakanishi, Takeo;Natarajan, Karthika;Safren, Lowell;Hamburger, Anne W.;Hussain, Arif;Ross, Douglas D.
• 通讯作者: Ross, Douglas D.