Supraphysiological Androgens Repress Prostate Cancer Growth and Induce DNA Damage Augmented by PARP Inhibition
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE119598 | GEO | 2019/07/09
REPOSITORIES: GEO
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Project description:The androgen receptor (AR) pathway regulates key cell survival programs in prostate epithelium. Targeting the AR has a remarkable therapeutic index and represents a near-universal driver and therapeutic vulnerability in metastatic prostate cancer. Though most approaches directed toward the AR focus on inhibiting AR signaling, laboratory and now clinical data have shown that high dose, supraphysiological androgen treatment (SPA), results in growth repression and improved out-comes in subsets of prostate cancer patients. However, the mechanism(s) contributing to SPA re-sponse and resistance remain unclear. To characterize SPA signaling, we integrated metrics of gene expression changes induced by SPA together with cistrome data and protein-interactomes. These analyses determined that the Dimerization partner, RB-like, E2F and Multi-vulval class B (DREAM) complex mediates growth repression and downregulation of E2F targets in response to SPA. Notably, prostate cancers with complete genomic loss of RB1 responded to SPA treatment whereas loss of DREAM complex components such as RBL1/2 promoted resistance. Overexpres-sion of MYC resulted in complete resistance to SPA and attenuated the SPA/AR-mediated repres-sion of E2F target genes. These findings support a model of SPA-mediated growth repression that relies on the negative regulation of MYC by AR leading to repression of E2F1 signaling via the DREAM-SIN3A-HDAC complex. As RB1 and DREAM complex stability are regulated by MYC, a key determinant of tumor sensitivity to SPA, treatment may hinge on effectively repress-ing MYC activity. The integrity of MYC signaling and DREAM complex assembly may conse-quently serve as determinants of SPA responses and as pathways mediating SPA resistance.
2023-05-26 | GSE228896 | GEO
Project description:The androgen receptor (AR) pathway regulates key cell survival programs in prostate epithelium. Targeting the AR has a remarkable therapeutic index and represents a near-universal driver and therapeutic vulnerability in metastatic prostate cancer. Though most approaches directed toward the AR focus on inhibiting AR signaling, laboratory and now clinical data have shown that high dose, supraphysiological androgen treatment (SPA), results in growth repression and improved out-comes in subsets of prostate cancer patients. However, the mechanism(s) contributing to SPA re-sponse and resistance remain unclear. To characterize SPA signaling, we integrated metrics of gene expression changes induced by SPA together with cistrome data and protein-interactomes. These analyses determined that the Dimerization partner, RB-like, E2F and Multi-vulval class B (DREAM) complex mediates growth repression and downregulation of E2F targets in response to SPA. Notably, prostate cancers with complete genomic loss of RB1 responded to SPA treatment whereas loss of DREAM complex components such as RBL1/2 promoted resistance. Overexpres-sion of MYC resulted in complete resistance to SPA and attenuated the SPA/AR-mediated repres-sion of E2F target genes. These findings support a model of SPA-mediated growth repression that relies on the negative regulation of MYC by AR leading to repression of E2F1 signaling via the DREAM-SIN3A-HDAC complex. As RB1 and DREAM complex stability are regulated by MYC, a key determinant of tumor sensitivity to SPA, treatment may hinge on effectively repress-ing MYC activity. The integrity of MYC signaling and DREAM complex assembly may conse-quently serve as determinants of SPA responses and as pathways mediating SPA resistance.
2023-05-26 | GSE228895 | GEO
Project description:The androgen receptor (AR) pathway regulates key cell survival programs in prostate epithelium. Targeting the AR has a remarkable therapeutic index and represents a near-universal driver and therapeutic vulnerability in metastatic prostate cancer. Though most approaches directed toward the AR focus on inhibiting AR signaling, laboratory and now clinical data have shown that high dose, supraphysiological androgen treatment (SPA), results in growth repression and improved outcomes in subsets of prostate cancer patients. However, the mechanism(s) contributing to SPA response and resistance remain unclear. To characterize SPA signaling, we integrated metrics of gene expression changes induced by SPA together with cistrome data and protein-interactomes. These analyses determined that the Dimerization partner, RB-like, E2F and Multi-vulval class B (DREAM) complex mediates growth repression and downregulation of E2F targets in response to SPA. Notably, prostate cancers with complete genomic loss of RB1 responded to SPA treat-ment whereas loss of DREAM complex components such as RBL1/2 promoted resistance. Over-expression of MYC resulted in complete resistance to SPA and attenuated the SPA/AR-mediated repression of E2F target genes. These findings support a model of SPA-mediated growth repression that relies on the negative regulation of MYC by AR leading to repression of E2F1 signaling via the DREAM-SIN3A-HDAC complex. As RB1 and DREAM complex stabil-ity are regulated by MYC, a key determinant of tumor sensitivity to SPA, treatment may hinge on effectively repressing MYC activity. The integrity of MYC signaling and DREAM complex assembly may consequently serve as determinants of SPA responses and as pathways mediating SPA resistance.
2023-05-26 | GSE225481 | GEO
Project description:Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously demonstrated that the cyclical administration of supraphysiological androgen (SPA), entitled Bipolar Androgen Therapy (BAT), can result in tumor regression and clinical benefit for patients with castration-resistant prostate cancer. However, predictors and mechanisms of response and resistance have been ill-defined. Here we show that growth inhibition of prostate cancer models by SPA requires high androgen receptor (AR) activity and is driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pre-treatment AR activity predicts downregulation of MYC, clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which is shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance can be overcome by alternating SPA with the AR inhibitor enzalutamide, which induces adaptive upregulation of AR and re-sensitizes prostate cancer to SPA. This work identifies high AR activity score as a predictive biomarker of response to BAT and supports a new treatment paradigm for prostate cancer involving alternating between AR inhibition and activation
2023-04-12 | GSE229555 | GEO
Project description:Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously demonstrated that the cyclical administration of supraphysiological androgen (SPA), entitled Bipolar Androgen Therapy (BAT), can result in tumor regression and clinical benefit for patients with castration-resistant prostate cancer. However, predictors and mechanisms of response and resistance have been ill-defined. Here we show that growth inhibition of prostate cancer models by SPA requires high androgen receptor (AR) activity and is driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pre-treatment AR activity predicts downregulation of MYC, clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which is shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance can be overcome by alternating SPA with the AR inhibitor enzalutamide, which induces adaptive upregulation of AR and re-sensitizes prostate cancer to SPA. This work identifies high AR activity score as a predictive biomarker of response to BAT and supports a new treatment paradigm for prostate cancer involving alternating between AR inhibition and activation
2022-11-01 | GSE213443 | GEO
Project description:Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously demonstrated that the cyclical administration of supraphysiological androgen (SPA), entitled Bipolar Androgen Therapy (BAT), can result in tumor regression and clinical benefit for patients with castration-resistant prostate cancer. However, predictors and mechanisms of response and resistance have been ill-defined. Here we show that growth inhibition of prostate cancer models by SPA requires high androgen receptor (AR) activity and is driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pre-treatment AR activity predicts downregulation of MYC, clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which is shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance can be overcome by alternating SPA with the AR inhibitor enzalutamide, which induces adaptive upregulation of AR and re-sensitizes prostate cancer to SPA. This work identifies high AR activity score as a predictive biomarker of response to BAT and supports a new treatment paradigm for prostate cancer involving alternating between AR inhibition and activation
2022-11-01 | GSE213437 | GEO
Project description:Supraphysiological Androgens Repress Prostate Cancer Growth and Induce DNA Damage Augmented by PARP Inhibition
| PRJNA489692 | ENA
Project description:Elk1 directs selective gene induction that is a substantial and critical component of growth signaling by AR in PC cells. Gene expression in LNCaP cells was determined in androgen-depleted medium in response to R1881 in ELK1 knock down (via AR shRNA) or in cells treated with control shRNA.
2013-05-02 | E-GEOD-34589 | biostudies-arrayexpress
Project description:The androgen receptor (AR) is a key driver of prostate cancer (PC), even in the state of castration-resistant PC (CRPC), and frequently even after treatment with second-line hormonal therapies such as abiraterone and enzalutamide. The persistence of AR activity via both ligand-dependent and ligand-independent (including constitutively active AR splice variants) mechanisms highlights the unmet need for alternative approaches to block AR signaling in CRPC. We investigated the transcription factor GATA2 as a regulator of AR signaling and a novel therapeutic target in PC. We demonstrate that GATA2 directly promotes AR expression (both full-length and splice variant), resulting in a strong positive correlation between GATA2 and AR expression in PC (cell lines and patient specimens). Conversely, GATA2 expression is repressed by androgen and AR, suggesting a negative feedback regulatory loop that, upon androgen deprivation, derepresses GATA2 to contribute to AR overexpression in CRPC. Simultaneously, GATA2 is necessary for optimal transcriptional activity of AR (both full-length and splice variant). GATA2 co-localizes with AR and FOXA1 on chromatin to enhance recruitment of steroid receptor coactivators (SRCs) and formation of the transcriptional holocomplex. In agreement with these important functions, high GATA2 expression and transcriptional activity predicted for worse clinical outcome in PC patients. A GATA2 small molecule inhibitor suppressed the expression and transcriptional function of AR (both full-length and splice variant) and exerted potent anticancer activity against PC cell lines. We propose pharmacological inhibition of GATA2 as a “first-in-field” approach to target AR expression and function and improve outcomes in CRPC. LNCaP cells were transfected with control siRNA (3), GATA2 siRNA (3) or AR siRNA for 72 hours.
2015-01-21 | E-GEOD-63539 | biostudies-arrayexpress
Project description:The androgen receptor (AR) is a therapeutic target of prostate cancer (PCa). Targeted AR therapy commonly uses androgen deprivation therapy (ADT) and AR antagonists to reduce androgen levels and inhibit tumor growth. Surprisingly, treatment with supraphysiological androgen level (SAL) can also inhibit the growth of PCa. SAL (R1881) was shown to induce cellular senescence in PCa. Knockdown of BHLHE40 in C4-2 and LNCaP cell lines indicates that BHLHE40 mediates SAL-induced cellular senescence as a possible tumor suppressive pathway. The RNA-seq from BHLHE40 knocked down C4-2 cells confirmed that BHLHE40 regulates cellular senescence and associated pathways. Interestingly, a large overlap of differentially expressed gene sets was identified between BHLHE40 regulated transcriptome and the SAL-changed transcriptome leading to four classes of up-and downregulated BHLHE40 transcriptome landscapes overlapping with that of AR. Further RNA-seq analyses revealed that the tumor suppressive cyclin G2 (CCNG2) emerged as a novel downstream target of BHLHE40. Knockdown of CCNG2 suggests that it mediates SAL-induced cellular senescence providing evidence of a novel pathway by the AR-BHLHE40-CCNG2 axis to mediate androgen-induced cellular senescence as a novel tumor suppressive pathway in PCa cells.
2024-06-21 | GSE262117 | GEO