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  • 1
    Online Resource
    Online Resource
    Androgen Receptor Inhibits Estrogen Receptor-α Activity and Is Prognostic in Breast Cancer
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 15 ( 2009-08-01), p. 6131-6140
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 15 ( 2009-08-01), p. 6131-6140
    Abstract: There is emerging evidence that the balance between estrogen receptor-α (ERα) and androgen receptor (AR) signaling is a critical determinant of growth in the normal and malignant breast. In this study, we assessed AR status in a cohort of 215 invasive ductal breast carcinomas. AR and ERα were coexpressed in the majority (80-90%) of breast tumor cells. Kaplan-Meier product limit analysis and multivariate Cox regression showed that AR is an independent prognostic factor in ERα-positive disease, with a low level of AR (less than median of 75% positive cells) conferring a 4.6-fold increased risk of cancer-related death (P = 0.002). Consistent with a role for AR in breast cancer outcome, AR potently inhibited ERα transactivation activity and 17β-estradiol–stimulated growth of breast cancer cells. Transfection of MDA-MB-231 breast cancer cells with either functionally impaired AR variants or the DNA-binding domain of the AR indicated that the latter is both necessary and sufficient for inhibition of ERα signaling. Consistent with molecular modeling, electrophoretic mobility shift assays showed binding of the AR to an estrogen-responsive element (ERE). Evidence for a functional interaction of the AR with an ERE in vivo was provided by chromatin immunoprecipitation data, revealing recruitment of the AR to the progesterone receptor promoter in T-47D breast cancer cells. We conclude that, by binding to a subset of EREs, the AR can prevent activation of target genes that mediate the stimulatory effects of 17β-estradiol on breast cancer cells. [Cancer Res 2009;69(15):6131–40]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-09-0452
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 2
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    Synthesis and fluorine-18 radiolabeling of a phospholipid as a PET imaging agent for prostate cancer
    Elsevier BV ; 2021
    In:  Nuclear Medicine and Biology Vol. 93 ( 2021-02), p. 37-45
    Details
    In: Nuclear Medicine and Biology, Elsevier BV, Vol. 93 ( 2021-02), p. 37-45
    Type of Medium: Online Resource
    ISSN: 0969-8051
    URL: Article
    DOI: 10.1016/j.nucmedbio.2020.11.007
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 1498538-X
    SSG: 12
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  • 3
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    Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis
    eLife Sciences Publications, Ltd ; 2020
    In:  eLife Vol. 9 ( 2020-07-20)
    Details
    In: eLife, eLife Sciences Publications, Ltd, Vol. 9 ( 2020-07-20)
    Abstract: Fatty acid β-oxidation (FAO) is the main bioenergetic pathway in human prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, encoding the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival. DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown selectively inhibited β-oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation and metastasis in mouse xenograft models. Mechanistically, targeting of DECR1 caused cellular accumulation of PUFAs, enhanced mitochondrial oxidative stress and lipid peroxidation, and induced ferroptosis. These findings implicate PUFA oxidation via DECR1 as an unexplored facet of FAO that promotes survival of PCa cells.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    URL: Article
    DOI: 10.7554/eLife.54166
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2020
    detail.hit.zdb_id: 2687154-3
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  • 4
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    Minireview: The Contribution of Different Androgen Receptor Domains to Receptor Dimerization and Signaling
    The Endocrine Society ; 2008
    In:  Molecular Endocrinology Vol. 22, No. 11 ( 2008-11-01), p. 2373-2382
    Details
    In: Molecular Endocrinology, The Endocrine Society, Vol. 22, No. 11 ( 2008-11-01), p. 2373-2382
    Type of Medium: Online Resource
    ISSN: 0888-8809 , 1944-9917
    URL: Article
    DOI: 10.1210/me.2008-0017
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2008
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  • 5
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    Evaluation of Small Molecule Drug Uptake in Patient-Derived Prostate Cancer Explants by Mass Spectrometry
    Springer Science and Business Media LLC ; 2019
    In:  Scientific Reports Vol. 9, No. 1 ( 2019-10-18)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2019-10-18)
    Abstract: Patient-derived explant (PDE) culture of solid tumors is increasingly being applied to preclinical evaluation of novel therapeutics and for biomarker discovery. In this technique, treatments are added to culture medium and penetrate the tissue via a gelatin sponge scaffold. However, the penetration profile and final concentrations of small molecule drugs achieved have not been determined to date. Here, we determined the extent of absorption of the clinical androgen receptor antagonist, enzalutamide, into prostate PDEs, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and matrix-assisted laser/desorption ionisation (MALDI) mass spectrometry imaging (MSI). In a cohort of 11 PDE tissues from eight individual patients, LC-MS/MS quantification of PDE homogenates confirmed enzalutamide (10 µM) uptake by all PDEs, which reached maximal average tissue concentration of 0.24–0.50 ng/µg protein after 48 h culture. Time dependent uptake of enzalutamide (50 µM) in PDEs was visualized using MALDI MSI over 24–48 h, with complete penetration throughout tissues evident by 6 h of culture. Drug signal intensity was not homogeneous throughout the tissues but had areas of markedly high signal that corresponded to drug target (androgen receptor)-rich epithelial regions of tissue. In conclusion, application of MS-based drug quantification and visualization in PDEs, and potentially other 3-dimensional model systems, can provide a more robust basis for experimental study design and interpretation of pharmacodynamic data.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-019-51549-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
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  • 6
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    Online Resource
    ELOVL5 Is a Critical and Targetable Fatty Acid Elongase in Prostate Cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 7 ( 2021-04-01), p. 1704-1718
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 7 ( 2021-04-01), p. 1704-1718
    Abstract: The androgen receptor (AR) is the key oncogenic driver of prostate cancer, and despite implementation of novel AR targeting therapies, outcomes for metastatic disease remain dismal. There is an urgent need to better understand androgen-regulated cellular processes to more effectively target the AR dependence of prostate cancer cells through new therapeutic vulnerabilities. Transcriptomic studies have consistently identified lipid metabolism as a hallmark of enhanced AR signaling in prostate cancer, yet the relationship between AR and the lipidome remains undefined. Using mass spectrometry–based lipidomics, this study reveals increased fatty acyl chain length in phospholipids from prostate cancer cells and patient-derived explants as one of the most striking androgen-regulated changes to lipid metabolism. Potent and direct AR-mediated induction of ELOVL fatty acid elongase 5 (ELOVL5), an enzyme that catalyzes fatty acid elongation, was demonstrated in prostate cancer cells, xenografts, and clinical tumors. Assessment of mRNA and protein in large-scale data sets revealed ELOVL5 as the predominant ELOVL expressed and upregulated in prostate cancer compared with nonmalignant prostate. ELOVL5 depletion markedly altered mitochondrial morphology and function, leading to excess generation of reactive oxygen species and resulting in suppression of prostate cancer cell proliferation, 3D growth, and in vivo tumor growth and metastasis. Supplementation with the monounsaturated fatty acid cis-vaccenic acid, a direct product of ELOVL5 elongation, reversed the oxidative stress and associated cell proliferation and migration effects of ELOVL5 knockdown. Collectively, these results identify lipid elongation as a protumorigenic metabolic pathway in prostate cancer that is androgen-regulated, critical for metastasis, and targetable via ELOVL5. Significance: This study identifies phospholipid elongation as a new metabolic target of androgen action that is critical for prostate tumor metastasis.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-20-2511
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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    detail.hit.zdb_id: 410466-3
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  • 7
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    Dual Roles of PARP-1 Promote Cancer Growth and Progression
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Discovery Vol. 2, No. 12 ( 2012-12-01), p. 1134-1149
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 2, No. 12 ( 2012-12-01), p. 1134-1149
    Abstract: PARP-1 is an abundant nuclear enzyme that modifies substrates by poly(ADP-ribose)-ylation. PARP-1 has well-described functions in DNA damage repair and also functions as a context-specific regulator of transcription factors. With multiple models, data show that PARP-1 elicits protumorigenic effects in androgen receptor (AR)–positive prostate cancer cells, in both the presence and absence of genotoxic insult. Mechanistically, PARP-1 is recruited to sites of AR function, therein promoting AR occupancy and AR function. It was further confirmed in genetically defined systems that PARP-1 supports AR transcriptional function, and that in models of advanced prostate cancer, PARP-1 enzymatic activity is enhanced, further linking PARP-1 to AR activity and disease progression. In vivo analyses show that PARP-1 activity is required for AR function in xenograft tumors, as well as tumor cell growth in vivo and generation and maintenance of castration resistance. Finally, in a novel explant system of primary human tumors, targeting PARP-1 potently suppresses tumor cell proliferation. Collectively, these studies identify novel functions of PARP-1 in promoting disease progression, and ultimately suggest that the dual functions of PARP-1 can be targeted in human prostate cancer to suppress tumor growth and progression to castration resistance. Significance: These studies introduce a paradigm shift with regard to PARP-1 function in human malignancy, and suggest that the dual functions of PARP-1 in DNA damage repair and transcription factor regulation can be leveraged to suppress pathways critical for promalignant phenotypes in prostate cancer cells by modulation of the DNA damage response and hormone signaling pathways. The combined studies highlight the importance of dual PARP-1 function in malignancy and provide the basis for therapeutic targeting. Cancer Discov; 2(12); 1134–49. ©2012 AACR. This article is highlighted in the In This Issue feature, p. 1065
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-12-0120
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2607892-2
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  • 8
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    Dysregulated fibronectin trafficking by Hsp90 inhibition restricts prostate cancer cell invasion
    Springer Science and Business Media LLC ; 2018
    In:  Scientific Reports Vol. 8, No. 1 ( 2018-02-01)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2018-02-01)
    Abstract: The molecular chaperone Hsp90 is overexpressed in prostate cancer (PCa) and is responsible for the folding, stabilization and maturation of multiple oncoproteins, which are implicated in PCa progression. Compared to first-in-class Hsp90 inhibitors such as 17-allylamino-demethoxygeldanamycin (17-AAG) that were clinically ineffective, second generation inhibitor AUY922 has greater solubility and efficacy. Here, transcriptomic and proteomic analyses of patient-derived PCa explants identified cytoskeletal organization as highly enriched with AUY922 treatment. Validation in PCa cell lines revealed that AUY922 caused marked alterations to cell morphology, and suppressed cell motility and invasion compared to vehicle or 17-AAG, concomitant with dysregulation of key extracellular matrix proteins such as fibronectin (FN1). Interestingly, while the expression of FN1 was increased by AUY922, FN1 secretion was significantly decreased. This resulted in cytosolic accumulation of FN1 protein within late endosomes, suggesting that AUY922 disrupts vesicular secretory trafficking pathways. Depletion of FN1 by siRNA knockdown markedly reduced the invasive capacity of PCa cells, phenocopying AUY922. These results highlight a novel mechanism of action for AUY922 beyond its established effects on cellular mitosis and survival and, furthermore, identifies extracellular matrix cargo delivery as a potential therapeutic target for the treatment of aggressive PCa.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-018-19871-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2615211-3
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  • 9
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    Abstract CN08-05: A combinatorial approach to targeting androgen receptor signaling in prostate cancer.
    American Association for Cancer Research (AACR) ; 2011
    In:  Molecular Cancer Therapeutics Vol. 10, No. 11_Supplement ( 2011-11-12), p. CN08-05-CN08-05
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 11_Supplement ( 2011-11-12), p. CN08-05-CN08-05
    Abstract: When androgen deprivation therapy (ADT) for prostate cancer fails and the disease progresses to a castrate-resistant state (castrate-resistant prostate cancer; CRPC), therapeutic options for patients are limited. It is now recognized that the majority of CRPC still express the androgen receptor (AR) and remain dependent on AR signaling for growth and survival. To limit growth or evolution of AR-dependent disease and thereby improve patient survival, we propose that a treatment strategy that simultaneously targets multiple features of the AR signaling axis will more effectively eliminate AR-dependent prostate cancer cells than single agent treatment strategies. We have shown that pharmacologically low doses of an AR antagonist (bicalutamide) in combination with either a heat shock protein 90 inhibitor (Hsp90i; 17-AAG) or a histone deacetylase inhibitor (vorinostat), results in synergistic growth suppression and induction of caspase-dependent death in AR-dependent prostate cancer cells. These drug combinations did not alter steady state protein levels of the AR, but suppressed AR activity, as evidenced by reduced prostate specific antigen levels. As expected, the drug combinations were not effective in androgen-independent, AR negative prostate cancer cells. To elucidate the mechanisms of drug synergy, we performed microarray studies to identify genetic programs modulated by each combination therapy or bicalutamide alone. Resultant data suggest that the combination treatments did not markedly enhance abrogation of androgen signaling compared with bicalutamide alone. Rather, the combination treatments regulated the expression of unique gene sets that were enriched for cell cycle, apoptosis, MAPK and insulin signaling compared to individual agents. To assess the potential efficacy of the combinatorial approach in human disease, we have developed a unique approach to study human prostate cancer where tumor specimens collected from men undergoing radical prostatectomy are cultured as explants for up to 7 days with maintenance of tissue integrity, cell proliferation and androgen signaling. Using this ex vivo strategy, we demonstrated that human prostate tumor tissue responds to the novel synthetic Hsp90 inhibitors (HSP990 and AUY922) with a marked reduction in proliferation and AR levels. Importantly, these studies have revealed a dissociation between client protein modulation (i.e. the established clinical biomarker of Hsp90 inhibition, HSP70) and proliferative response to Hsp90 inhibition, which was not seen in prostate cancer cell lines in vitro. Collectively, these findings suggest that the ex vivo methodology may better predict individual patient response to Hsp90 inhibitors and could be useful as a pre-clinical model of drug development, including identification of robust biomarkers of response. Currently we are using human tumor explants to identify optimal combinations of AR-targeting agents and potential markers of response. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr CN08-05.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-11-CN08-05
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2062135-8
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  • 10
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    Maximizing the Therapeutic Potential of HSP90 Inhibitors
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Research Vol. 13, No. 11 ( 2015-11-01), p. 1445-1451
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 13, No. 11 ( 2015-11-01), p. 1445-1451
    Abstract: HSP90 is required for maintaining the stability and activity of a diverse group of client proteins, including protein kinases, transcription factors, and steroid hormone receptors involved in cell signaling, proliferation, survival, oncogenesis, and cancer progression. Inhibition of HSP90 alters the HSP90-client protein complex, leading to reduced activity, misfolding, ubiquitination, and, ultimately, proteasomal degradation of client proteins. HSP90 inhibitors have demonstrated significant antitumor activity in a wide variety of preclinical models, with evidence of selectivity for cancer versus normal cells. In the clinic, however, the efficacy of this class of therapeutic agents has been relatively limited to date, with promising responses mainly observed in breast and lung cancer, but no major activity seen in other tumor types. In addition, adverse events and some significant toxicities have been documented. Key to improving these clinical outcomes is a better understanding of the cellular consequences of inhibiting HSP90 that may underlie treatment response or resistance. This review considers the recent progress that has been made in the study of HSP90 and its inhibitors and highlights new opportunities to maximize their therapeutic potential. Mol Cancer Res; 13(11); 1445–51. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-15-0234
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2097884-4
    SSG: 12
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