Myc confers androgen-independent prostate cancer cell growth

Bernard, David; Pourtier-Manzanedo, Albin; Gil, Jesús; Beach, David

doi:10.1172/jci200319035

Cited by 179 publications

(47 citation statements)

References 37 publications

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“…Myc amplification is specifically observed in castration resistant tumors (54, 56). Bernard et al demonstrated that Myc overexpression in the hormone-sensitive LNCaP line confers resistance to androgen deprivation or AR knockdown (109). Conversely, AR knockdown decreases Myc expression, indicating Myc is downstream of AR.…”

Section: Mycmentioning

confidence: 99%

Disruption of Prostate Epithelial Differentiation Pathways and Prostate Cancer Development

Frank

Miranti

2013

Front. Oncol.

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One of the foremost problems in the prostate cancer (PCa) field is the inability to distinguish aggressive from indolent disease, which leads to difficult prognoses and thousands of unnecessary surgeries. This limitation stems from the fact that the mechanisms of tumorigenesis in the prostate are poorly understood. Some genetic alterations are commonly reported in prostate tumors, including upregulation of Myc, fusion of Ets genes to androgen-regulated promoters, and loss of Pten. However, the specific roles of these aberrations in tumor initiation and progression are poorly understood. Likewise, the cell of origin for PCa remains controversial and may be linked to the aggressive potential of the tumor. One important clue is that prostate tumors co-express basal and luminal protein markers that are restricted to their distinct cell types in normal tissue. Prostate epithelium contains layer-specific stem cells as well as rare bipotent cells, which can differentiate into basal or luminal cells. We hypothesize that the primary oncogenic cell of origin is a transient-differentiating bipotent cell. Such a cell must maintain tight temporal and spatial control of differentiation pathways, thus increasing its susceptibility for oncogenic disruption. In support of this hypothesis, many of the pathways known to be involved in prostate differentiation can be linked to genes commonly altered in PCa. In this article, we review what is known about important differentiation pathways (Myc, p38MAPK, Notch, PI3K/Pten) in the prostate and how their misregulation could lead to oncogenesis. Better understanding of normal differentiation will offer new insights into tumor initiation and may help explain the functional significance of common genetic alterations seen in PCa. Additionally, this understanding could lead to new methods for classifying prostate tumors based on their differentiation status and may aid in identifying more aggressive tumors.

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Section: Mycmentioning

confidence: 99%

Disruption of Prostate Epithelial Differentiation Pathways and Prostate Cancer Development

Frank

Miranti

2013

Front. Oncol.

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“…This function of BRD proteins is best characterized through their role in regulating oncogenic c-MYC transcriptional activity (13). Treatment with pharmacologic BET inhibitors such as JQ1 leads to suppression of c-MYC transcription, an oncogene shown to convey androgenindependent growth of prostate cancer cells and upregulated in CRPC (14,15), followed by genome-wide downregulation of Myc-dependent target genes (13). Given the effects of BET inhibitors on prostate cancer, JQ1 is a seemingly attractive candidate for clinical translation but is limited by off-target effects, such as binding to the proteins DDB1 and RAD23B (hHR23b) as well as toxicity (16).…”

Section: Introductionmentioning

confidence: 99%

Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer

Kregel

Malik

Asangani

et al. 2019

Clinical Cancer Research

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Purpose: The bromodomain and extraterminal (BET)containing proteins (BRD2/3/4) are essential epigenetic coregulators for prostate cancer growth. BRD inhibitors have shown promise for treatment of metastatic castration-resistant prostate cancer (mCRPC), and have been shown to function even in the context of resistance to next-generation AR-targeted therapies such as enzalutamide and abiraterone. Their clinical translation, however, has been limited by off-target effects, toxicity, and rapid resistance.Experimental Design: We have developed a series of molecules that target BET bromodomain proteins through their proteasomal degradation, improving efficacy and specificity of standard inhibitors. We tested their efficacy by utilizing prostate cancer cell lines and patient-derived xenografts, as well as several techniques including RNA-sequencing, mass spectroscopic proteomics, and lipidomics.Results: BET degraders function in vitro and in vivo to suppress prostate cancer growth. These drugs preferentially affect AR-positive prostate cancer cells (22Rv1, LNCaP, VCaP) over AR-negative cells (PC3 and DU145), and proteomic and genomic mechanistic studies confirm disruption of oncogenic AR and MYC signaling at lower concentrations than BET inhibitors. We also identified increases in polyunsaturated fatty acids (PUFA) and thioredoxin-interacting protein (TXNIP) as potential pharmacodynamics biomarkers for targeting BET proteins.Conclusions: Compounds inducing the pharmacologic degradation of BET proteins effectively target the major oncogenic drivers of prostate cancer, and ultimately present a potential advance in the treatment of mCRPC. In particular, our compound dBET-3, is most suited for further clinical development.

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“…Furthermore, LNCaP cells exposed only to FN displayed higher expression levels of MYC, upregulation of which is related to early stages of PCa, required for AR-dependent growth and related to the development of metastatic progression in PCa [49,50]. Thus, we propose that when FN is the predominant element, tumor cells can develop invasive behavior and resistance to apoptosis.…”

Section: Discussionmentioning

confidence: 81%

Basement membrane extract attenuates the more malignant gene expression profile accentuated by fibronectin in prostate cancer cells

et al. 2018

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Prostate cancer (PCa) has high mortality rates, with most of the deaths resulting from the development of metastasis. Fibronectin (FN) plays key roles in cell adhesion and affects the migratory behavior of cells. In the tumor microenvironment and also in the blood plasma during metastasis, FN displays increased expression, however its role in prostate cancer remains poorly understood. This study aimed to unveil the specific roles of FN as a soluble component, alone or in combination with a complex basement membrane. To investigate the impact of FN in neoplastic prostate cells, we evaluated the gene expression of LNCaP cells by RT-qPCR after exposure to soluble FN (25 µg/mL) either alone or in combination with a basement membrane. When FN was the predominant matrix element, such as in blood plasma, PCa tumor cells increased their expression of genes related to an invasive behavior and resistance to apoptosis, including CDH2, ITGA5, AKT1, and BCL2. However, the combined presence of FN and a complex basement membrane had the opposite effect on LNCaP cells, in which the expression levels of CDH2, ITGA5, AKT1, and BCL2 were reduced. Hierarchical clustering analysis with LNCaP and RWPE-1 cells showed that LNCaP cells exposed to an enriched extracellular matrix displayed an expression pattern more similar to that shown by RWPE-1 cells, a cell line that illustrates characteristics of the normal prostate epithelium. These findings provide the groundwork for future studies addressing the role of FN in tumor growth, particularly in the context of cancer evolution/progression from a solid primary tumor to a transitory circulating state.

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Myc confers androgen-independent prostate cancer cell growth

Cited by 179 publications

References 37 publications

Disruption of Prostate Epithelial Differentiation Pathways and Prostate Cancer Development

Disruption of Prostate Epithelial Differentiation Pathways and Prostate Cancer Development

Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer

Basement membrane extract attenuates the more malignant gene expression profile accentuated by fibronectin in prostate cancer cells

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