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  • 1
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    Online Resource
    Semaphorin 3C promotes de novo steroidogenesis in prostate cancer cells
    Bioscientifica ; 2023
    In:  Endocrine-Related Cancer ( 2023-10)
    Details
    In: Endocrine-Related Cancer, Bioscientifica, ( 2023-10)
    Abstract: Intratumoral androgen biosynthesis contributes to castration-resistant prostate cancer progression in patients treated with androgen deprivation therapy. The molecular mechanisms by which castration-resistant prostate cancer acquire the capacity for androgen biosynthesis to bypass androgen deprivation therapy are not entirely known. Here, we show that Semaphorin 3C, a secreted signaling protein that is highly expressed in castration-resistant prostate cancer, can promote steroidogenesis by altering the expression profile of key steroidogenic enzymes. Semaphorin 3C, not only upregulates enzymes required for androgen synthesis from dehydroepiandrosterone or de novo from cholesterol, but also simultaneously downregulates enzymes involved in the androgen inactivation pathway. These changes in gene expression correlate with increased production of androgens induced by Semaphorin 3C in prostate cancer model cells. Moreover, Semaphorin 3C upregulates androgen synthesis in LNCaP cell-derived xenograft tumors, likely contributing to the enhanced in vivo tumor growth rate post-castration. Furthermore, Semaphorin 3C activates sterol regulatory element-binding protein, a transcription factor that upregulates enzymes involved in the synthesis of cholesterol, a sole precursor for de novo steroidogenesis. The ability of Semaphorin 3C to promote intratumoral androgen synthesis may be a key mechanism contributing to the reactivation of androgen receptor pathway in castration-resistant prostate cancer, conferring continued growth under androgen deprivation therapy. These findings identify Semaphorin 3C as a potential therapeutic target for suppressing intratumoral steroidogenesis.
    Type of Medium: Online Resource
    ISSN: 1351-0088 , 1479-6821
    URL: Article
    DOI: 10.1530/ERC-23-0010
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2023
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  • 2
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    Erythropoietin promotes functional recovery via anti-apoptotic mechanisms in mouse unilateral ureteral obstruction
    Springer Science and Business Media LLC ; 2020
    In:  Cell Stress and Chaperones Vol. 25, No. 2 ( 2020-03), p. 245-251
    Details
    In: Cell Stress and Chaperones, Springer Science and Business Media LLC, Vol. 25, No. 2 ( 2020-03), p. 245-251
    Type of Medium: Online Resource
    ISSN: 1355-8145 , 1466-1268
    URL: Article
    DOI: 10.1007/s12192-020-01067-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2002594-4
    SSG: 12
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  • 3
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    Multimodal biomarkers overcome sampling bias to predict presence of aggressive localized prostate cancer.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 6_suppl ( 2021-02-20), p. 209-209
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 6_suppl ( 2021-02-20), p. 209-209
    Abstract: 209 Background: Histopathologic investigation of diagnostic prostate biopsies both confirms the presence of disease and estimates its potential for distal spread via tumour grade. The accuracy of biopsy grading is limited by intra-tumoral heterogeneity, inter-observer variability, and other factors. To improve risk stratification at the time of diagnosis, we sought to create objective molecular biomarkers of radical prostatectomy grade that are resistant to sampling error and should be useful when applied to biopsy tissue. Methods: We developed and validated a robust objective biomarker of prostate cancer grade using pathologic grading of prostatectomy tissues as the gold standard. We created training (333 patients) and validation (202 patients) cohorts of Cancer of the Prostate Risk Assessment (CAPRA) low- and intermediate-risk prostate cancer patients. To address intra-tumoral heterogeneity, each tumor was sampled at two locations. We profiled the abundance of 342 mRNAs complemented by 100 canonical DNA copy number aberration loci (CNAs) and 14 hypermethylation events. Using the training cohort with cross-validation, we evaluated models for training classifiers of pathologic Grade Group ≥2, Restricting to strategies resulting in true negative rates ≥0.5, true positive (TP) rates ≥0.8, we selected two strategies to train classifiers, PRONTO-e and PRONTO-m. Results: The PRONTO-e classifier comprises 353 mRNA and CNA features, while the PRONTO-m classifier comprises 94 mRNA, CNA, methylation and clinical features. Both classifiers (PRONTO-e, PRONTO-m) validated in the independent cohort, with respective TP rates of 0.809 and 0.760, false positive rates of 0.429 and 0.262, F1 scores of 0.709 and 0.724, and AUCs of 0.792 and 0.818. Conclusions: Two classifiers were developed and validated in separate cohorts, each achieved excellent performance by integrating different types of molecular data. Implementation of classifiers with these performance characteristics could markedly improve current active surveillance approaches without increasing patient morbidity and may help better inform patients on their individual need for definitive therapy versus active surveillance.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.6_suppl.209
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 4
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    Transient Sox9 Expression Facilitates Resistance to Androgen-Targeted Therapy in Prostate Cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Clinical Cancer Research Vol. 26, No. 7 ( 2020-04-01), p. 1678-1689
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 7 ( 2020-04-01), p. 1678-1689
    Abstract: Patients with metastatic prostate cancer are increasingly presenting with treatment-resistant, androgen receptor–negative/low (AR−/Low) tumors, with or without neuroendocrine characteristics, in processes attributed to tumor cell plasticity. This plasticity has been modeled by Rb1/p53 knockdown/knockout and is accompanied by overexpression of the pluripotency factor, Sox2. Here, we explore the role of the developmental transcription factor Sox9 in the process of prostate cancer therapy response and tumor progression. Experimental Design: Unique prostate cancer cell models that capture AR−/Low stem cell–like intermediates were analyzed for features of plasticity and the functional role of Sox9. Human prostate cancer xenografts and tissue microarrays were evaluated for temporal alterations in Sox9 expression. The role of NF-κB pathway activity in Sox9 overexpression was explored. Results: Prostate cancer stem cell–like intermediates have reduced Rb1 and p53 protein expression and overexpress Sox2 as well as Sox9. Sox9 was required for spheroid growth, and overexpression increased invasiveness and neural features of prostate cancer cells. Sox9 was transiently upregulated in castration-induced progression of prostate cancer xenografts and was specifically overexpressed in neoadjuvant hormone therapy (NHT)–treated patient tumors. High Sox9 expression in NHT-treated patients predicts biochemical recurrence. Finally, we link Sox9 induction to NF-κB dimer activation in prostate cancer cells. Conclusions: Developmentally reprogrammed prostate cancer cell models recapitulate features of clinically advanced prostate tumors, including downregulated Rb1/p53 and overexpression of Sox2 with Sox9. Sox9 is a marker of a transitional state that identifies prostate cancer cells under the stress of therapeutic assault and facilitates progression to therapy resistance. Its expression may index the relative activity of the NF-κB pathway.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-19-0098
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    detail.hit.zdb_id: 2036787-9
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  • 5
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    Abstract 5283: Characterization of Gli activation by the estrogen receptor in breast cancer cells
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5283-5283
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5283-5283
    Abstract: Background: The nuclear steroid receptor superfamily encompasses a group of proteins best known fortheir functions as primary transcription factors that are conditionally active when bound to a ligand.Here, we show that a prominent member of this family, the estrogen receptor [ER-α] have a secondaryfunction of activating the Gli family of transcription factors. Gli is recognized as the mediator of activeHedgehog (Hh) signaling and plays an important role in cell development and growth. Gli activity isregulated by a post-translational proteolytic process that is suppressed by Hedgehog signaling.Previously we found that in prostate cancer, the ligand activated androgen receptor [AR] recognizes andbinds to Gli proteins at their Protein Processing Domains. This binding stabilizes Gli proteins in their un-proteolyzed active form and bypasses the Hedgehog signaling, thus promoting cancer progressionthrough non-canonical activation of Gli proteins. Due to the high similarity between AR and ER, wehypothesized that a similar Gli regulation could play a role in Breast Cancer (BrCA) progression. We thustested the ability of human ER-α to bind and activate Gli in BrCa and evaluated the role of this pathwayin tumor cell growth. Methods: we measured Gli activity in 293T and BrCa cells (MCF7, T47D, MDA-MB-453) in presence andabsence of steroid ligand using Gli-luciferase reporter assay. We evaluated the interaction between Gli3and ER-α by co-immunoprecipitation and proximity ligation assay and assessed the stability of Gli3stability in BrCa cell extracts by western blots. We also studied the effect of ER-α knockdown ordestabilization (by fulvestrant treatment) on Gli3 stability, formation of intranuclear ER-α-Gli3complexes and Gli reporter activity. We also measured the expression level of Gli target genes in thepresence and absence of estradiol by qPCR in BrCa cells. Lastly, we evaluated the importance of Gli3expression on BrCa growth by Gli3 knockdown and Cyquant assay. Results: We found that ER co-immunoprecipitates with Gli3. Transfection with ER-α increased Glireporter activity which was further increased by estradiol treatment. Acute (2hr) estradiol treatmentincreased intranuclear ER-α-Gli3 complex formation in BrCa cells. Chronic (48hr) estradiol treatmentincreased Gli3 stability and endogenous activity in BrCa cells. Destabilization or knockdown of ER-αdecreased estradiol-induced formation of ER-α-Gli3 complexes as well as Gli activity and stability in BrCacells. In addition, siRNA knockdown of Gli3 reduced growth in BrCa cells. Conclusion: Collectively our results uncovered a new role of the steroid receptors ER and AR inregulating Gli oncogenic transcriptional activity in BrCa and PCa, respectively. Citation Format: Shabnam Massah, Jane Foo, Na Li, Sarah Truong, Mannan Nouri, Lishi Xie, Gail Prins, Ralph Buttyan, Nada Lallous, Artem Cherkasov. Characterization of Gli activation by the estrogen receptor in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5283.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-5283
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 6
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    Abstract 3080: Characterization of steroid receptor mediated activation of GLI as driving force of breast cancer growth
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3080-3080
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3080-3080
    Abstract: Background: Hedgehog (Hh) signaling pathway plays a fundamental role in the early stages of development by regulating morphogenesis. GLI transcription factors are drivers of this signaling pathway by regulating the expression of growth related genes. Hyperactivation of GLI proteins have been associated with several cancers including medulloblastoma, glioblastoma, ovarian, prostate and breast cancers. Our study in breast cancer (BCa) suggests transcriptional activation of GLI3 in estrogen receptor alpha (ERα) positive cells upon estradiol stimulation. Loss of ERα greatly decreases GLI3 protein stability and stimulation with estradiol significantly increases GLI3 stability in ER-positive BCa cells. We have discovered that GLI3 forms nuclear complexes with ERα upon estradiol stimulation and that the loss of GLI3 reduces BCa cells growth. Therefore, we hypothesize that ERα-GLI3 complex orchestrates BCa transcriptome required for cell growth and development. Our study focuses on characterizing ERα mediated activation of GLI3 in BCa cells and the possible compensation by other steroid receptors such as the androgen receptor (AR) and the glucocorticoid receptor (GR) in ER-negative BCa cells. Method: We examined ERα- GLI transcriptional activity by RNA sequencing upon stimulation with estradiol and inhibition of GLI activity by GANT61 in ER-positive MCF7 cells. We also identified ERα domains that are essential for GLI3 binding by immunoprecipitation and proximity ligation assay (PLA). To identify ERα-GLI3 interactome, we have optimized Rapid Immunoprecipitation Mass Spectrometry of Endogenous protein (RIME). We also examined the role of GLI3 in ER-negative BCa cell growth and characterized the role of AR and GR in activating GLI3 by luciferase reporter assay.Results: Inhibition of GLI DNA binding by GANT61 reduced the expression of GLI regulated (CDC20, CDK1, UBE2C) and modified expression of ERα regulated (FOXM1, SPC24, KIF20A, BIRC5) genes, suggesting cooperative role of ERα-GLI3 in mediating growth and metastasis. The optimized RIME assay suggests immunoprecipitation of ERα with GLI3 in BCa cells upon estradiol induction. Immunoprecipitation and PLA studies suggest that ERα-N terminal, DNA binding and C-terminal domains interact with GLI3. We also showed that knockdown of GLI3 reduces growth in ER negative BCa cells and that AR or GR stimulation by dihydrotestosterone and dexamethasone respectively, are important for GLI3 transcriptional activity. Conclusion: Collectively, our results suggest a new role of steroid receptors in regulating GLI oncogenic transcriptional activity in BCa, leading to new therapeutic possibilities for patients. Citation Format: Shabnam Massah, Maria Guo, Jane Foo, Ralph Buttyan, Artem Cherkasov, Nada Lallous. Characterization of steroid receptor mediated activation of GLI as driving force of breast cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3080.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-3080
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 7
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    The long noncoding RNA H19 regulates tumor plasticity in neuroendocrine prostate cancer
    Springer Science and Business Media LLC ; 2021
    In:  Nature Communications Vol. 12, No. 1 ( 2021-12-21)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2021-12-21)
    Abstract: Neuroendocrine (NE) prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (PCa) arising either de novo or from transdifferentiated prostate adenocarcinoma following androgen deprivation therapy (ADT). Extensive computational analysis has identified a high degree of association between the long noncoding RNA (lncRNA) H19 and NEPC, with the longest isoform highly expressed in NEPC. H19 regulates PCa lineage plasticity by driving a bidirectional cell identity of NE phenotype (H19 overexpression) or luminal phenotype (H19 knockdown). It contributes to treatment resistance, with the knockdown of H19 re-sensitizing PCa to ADT. It is also essential for the proliferation and invasion of NEPC. H19 levels are negatively regulated by androgen signaling via androgen receptor (AR). When androgen is absent SOX2 levels increase, driving H19 transcription and facilitating transdifferentiation. H19 facilitates the PRC2 complex in regulating methylation changes at H3K27me3/H3K4me3 histone sites of AR-driven and NEPC-related genes. Additionally, this lncRNA induces alterations in genome-wide DNA methylation on CpG sites, further regulating genes associated with the NEPC phenotype. Our clinical data identify H19 as a candidate diagnostic marker and predictive marker of NEPC with elevated H19 levels associated with an increased probability of biochemical recurrence and metastatic disease in patients receiving ADT. Here we report H19 as an early upstream regulator of cell fate, plasticity, and treatment resistance in NEPC that can reverse/transform cells to a treatable form of PCa once therapeutically deactivated.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-021-26901-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2553671-0
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  • 8
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    Gli activation by the estrogen receptor in breast cancer cells: Regulation of cancer cell growth by Gli3
    Elsevier BV ; 2021
    In:  Molecular and Cellular Endocrinology Vol. 522 ( 2021-02), p. 111136-
    Details
    In: Molecular and Cellular Endocrinology, Elsevier BV, Vol. 522 ( 2021-02), p. 111136-
    Type of Medium: Online Resource
    ISSN: 0303-7207
    URL: Article
    DOI: 10.1016/j.mce.2020.111136
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 1500651-7
    SSG: 12
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  • 9
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    Abstract B046: Multimodal biomarkers that predict the presence of Gleason pattern 4: Potential impact for active surveillance
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 11_Supplement ( 2023-06-02), p. B046-B046
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 11_Supplement ( 2023-06-02), p. B046-B046
    Abstract: Purpose: Latent Grade Group (GG) ≥2 prostate cancer can impact the performance of active surveillance (AS) protocols. To date, molecular biomarkers for AS have relied solely on RNA or protein. We trained and independently validated multimodal (mRNA abundance, DNA methylation, and DNA copy number) biomarkers that more accurately separate GG1 from GG≥2 cancers. Materials and Methods: Low- and intermediate-risk prostate cancer patients were assigned to training (n=333) and validation (n=202) cohorts. We profiled the abundance of 342 mRNAs, 100 DNA copy number aberration (CNA) loci and 14 hypermethylation sites at two locations per tumor. Using the training cohort with cross- validation, we evaluated methods for training classifiers of pathologic GG≥2 in centrally reviewed radical prostectomies (RPs). We trained two distinct classifiers, PRONTO-e and PRONTO-m, and validated them in an independent RP cohort. Results: PRONTO-e comprises 353 mRNA and CNA features. PRONTO-m includes 94 clinical, mRNAs, CNAs and methylation features at 14 and 12 loci, respectively. In independent validation, PRONTO-e and PRONTO-m predicted GG≥2 with respective true positive rates of 0.81 and 0.76, false positive rates of 0.43 and 0.26. Both classifiers were resistant to sampling error and identified more upgraded men than a well-validated pre-surgical risk calculator, CAPRA (p & lt;0.001). Conclusions: Two GG classifiers with superior accuracy were developed by incorporating RNA and DNA features and validated in an independent cohort. Upon further validation in biopsy samples, classifiers with these performance characteristics could refine selection of men for AS, extending their treatment-free survival and intervals between surveillance. Citation Format: Anna Y. Lee, David M. Berman, Robert Lesurf, Palak G. Patel, Walead Ebrahimizadeh, Jane Bayani, Laura A. Lee, Nadia Boufaied, Shamini Selvarajah, Tamara Jamaspishvili, Karl-Philippe Guérard, Dan Dion, Atsunari Kawashima, Gina M. Clarke, Nathan How, Chelsea L. Jackson, Eleonora Scarlata, Khurram Siddiqui, John B.A. Okello, Armen G. Aprikian, Madeleine Moussa, Antonio Finelli, Joseph Chin, Fadi Brimo, Glenn Bauman, Andrew Loblaw, Vasundara Venkateswaran, Ralph Buttyan, Simone Chevalier, Axel Thomson, Paul C. Park, D. Robert Siemens, Jacques Lapointe, Paul C. Boutros, John M.S. Bartlett. Multimodal biomarkers that predict the presence of Gleason pattern 4: Potential impact for active surveillance [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B046.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PRCA2023-B046
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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