RESUMEN
Lung cancer is the deadliest malignancy in the United States. Non-small cell lung cancer (NSCLC) accounts for 85% of cases and is frequently driven by activating mutations in the gene encoding the KRAS GTPase (e.g., KRASG12D). Our previous work demonstrated that Argonaute 2 (AGO2)-a component of the RNA-induced silencing complex (RISC)-physically interacts with RAS and promotes its downstream signaling. We therefore hypothesized that AGO2 could promote KRASG12D-dependent NSCLC in vivo. To test the hypothesis, we evaluated the impact of Ago2 knockout in the KPC (LSL-KrasG12D/+;p53f/f;Cre) mouse model of NSCLC. In KPC mice, intratracheal delivery of adenoviral Cre drives lung-specific expression of a stop-floxed KRASG12D allele and biallelic ablation of p53 Simultaneous biallelic ablation of floxed Ago2 inhibited KPC lung nodule growth while reducing proliferative index and improving pathological grade. We next applied the KPHetC model, in which the Clara cell-specific CCSP-driven Cre activates KRASG12D and ablates a single p53 allele. In these mice, Ago2 ablation also reduced tumor size and grade. In both models, Ago2 knockout inhibited ERK phosphorylation (pERK) in tumor cells, indicating impaired KRAS signaling. RNA sequencing (RNA-seq) of KPC nodules and nodule-derived organoids demonstrated impaired canonical KRAS signaling with Ago2 ablation. Strikingly, accumulation of pERK in KPC organoids depended on physical interaction of AGO2 and KRAS. Taken together, our data demonstrate a pathogenic role for AGO2 in KRAS-dependent NSCLC. Given the prevalence of this malignancy and current difficulties in therapeutically targeting KRAS signaling, our work may have future translational relevance.
Asunto(s)
Proteínas Argonautas/fisiología , Carcinoma de Pulmón de Células no Pequeñas/etiología , Neoplasias Pulmonares/etiología , Proteínas Proto-Oncogénicas p21(ras)/fisiología , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Neoplasias Pulmonares/genética , Sistema de Señalización de MAP Quinasas , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/fisiologíaRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, employs two key host proteins to gain entry and replicate within cells, angiotensin-converting enzyme 2 (ACE2) and the cell surface transmembrane protease serine 2 (TMPRSS2). TMPRSS2 was first characterized as an androgen-regulated gene in the prostate. Supporting a role for sex hormones, males relative to females are disproportionately affected by COVID-19 in terms of mortality and morbidity. Several studies, including one employing a large epidemiological cohort, suggested that blocking androgen signaling is protective against COVID-19. Here, we demonstrate that androgens regulate the expression of ACE2, TMPRSS2, and androgen receptor (AR) in subsets of lung epithelial cells. AR levels are markedly elevated in males relative to females greater than 70 y of age. In males greater than 70 y old, smoking was associated with elevated levels of AR and ACE2 in lung epithelial cells. Transcriptional repression of the AR enhanceosome with AR or bromodomain and extraterminal domain (BET) antagonists inhibited SARS-CoV-2 infection in vitro. Taken together, these studies support further investigation of transcriptional inhibition of critical host factors in the treatment or prevention of COVID-19.
RESUMEN
The modern armamentarium for cancer treatment includes immunotherapy and targeted therapy, such as protein kinase inhibitors. However, the mechanisms that allow cancer-targeting drugs to effectively mobilize dendritic cells (DCs) and affect immunotherapy are poorly understood. Here, we report that among shared gene targets of clinically relevant protein kinase inhibitors, high PIKFYVE expression was least predictive of complete response in patients who received immune checkpoint blockade (ICB). In immune cells, high PIKFYVE expression in DCs was associated with worse response to ICB. Genetic and pharmacological studies demonstrated that PIKfyve ablation enhanced DC function via selectively altering the alternate/non-canonical NF-κB pathway. Both loss of Pikfyve in DCs and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively controls DCs, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.
RESUMEN
Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic cells (DC) and other myeloid cells with antigen presenting and cancer cell killing capacities is an attractive but not fully exploited approach. Here, we show that PIKFYVE is a shared gene target of clinically relevant protein kinase inhibitors and high expression of this gene in DCs is associated with poor patient response to immune checkpoint blockade (ICB) therapy. Genetic and pharmacological studies demonstrate that PIKfyve ablation enhances the function of CD11c+ cells (predominantly dendritic cells) via selectively altering the non-canonical NF-κB pathway. Both loss of Pikfyve in CD11c+ cells and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively regulates the function of CD11c+ cells, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.
Asunto(s)
Antígeno CD11c , Células Dendríticas , Morfolinas , Fosfatidilinositol 3-Quinasas , Animales , Femenino , Humanos , Ratones , Antígeno CD11c/metabolismo , Línea Celular Tumoral , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/efectos de los fármacos , Hidrazonas , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/métodos , Ratones Endogámicos C57BL , Morfolinas/farmacología , Neoplasias/inmunología , Neoplasias/genética , Neoplasias/terapia , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas , Linfocitos T/inmunología , MasculinoRESUMEN
Prostate cancer is an exemplar of an enhancer-binding transcription factor-driven disease. The androgen receptor (AR) enhanceosome complex comprised of chromatin and epigenetic coregulators assembles at enhancer elements to drive disease progression. The paralog lysine acetyltransferases p300 and CBP deposit histone marks that are associated with enhancer activation. Here, we demonstrate that p300/CBP are determinant cofactors of the active AR enhanceosome in prostate cancer. Histone H2B N-terminus multisite lysine acetylation (H2BNTac), which is exclusively reliant on p300/CBP catalytic function, marked active enhancers and was notably elevated in prostate cancer lesions relative to the adjacent benign epithelia. Degradation of p300/CBP rapidly depleted acetylation marks associated with the active AR enhanceosome, which was only partially phenocopied by inhibition of their reader bromodomains. Notably, H2BNTac was effectively abrogated only upon p300/CBP degradation, which led to a stronger suppression of p300/CBP-dependent oncogenic gene programs relative to bromodomain inhibition or the inhibition of its catalytic domain. In vivo experiments using an orally active p300/CBP proteolysis targeting chimera (PROTAC) degrader (CBPD-409) showed that p300/CBP degradation potently inhibited tumor growth in preclinical models of castration-resistant prostate cancer and synergized with AR antagonists. While mouse p300/CBP orthologs were effectively degraded in host tissues, prolonged treatment with the PROTAC degrader was well tolerated with no significant signs of toxicity. Taken together, our study highlights the pivotal role of p300/CBP in maintaining the active AR enhanceosome and demonstrates how target degradation may have functionally distinct effects relative to target inhibition, thus supporting the development of p300/CBP degraders for the treatment of advanced prostate cancer.
RESUMEN
Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a unique molecular subtype of metastatic castration-resistant prostate cancer (mCRPC). It remains unclear, however, whether CDK12 loss per se is sufficient to drive prostate cancer development-either alone, or in the context of other genetic alterations-and whether CDK12-mutant tumors exhibit sensitivity to specific pharmacotherapies. Here, we demonstrate that tissue-specific Cdk12 ablation is sufficient to induce preneoplastic lesions and robust T cell infiltration in the mouse prostate. Allograft-based CRISPR screening demonstrated that Cdk12 loss is positively associated with Trp53 inactivation but negatively associated with Pten inactivation-akin to what is observed in human mCRPC. Consistent with this, ablation of Cdk12 in prostate organoids with concurrent Trp53 loss promotes their proliferation and ability to form tumors in mice, while Cdk12 knockout in the Pten-null prostate cancer mouse model abrogates tumor growth. Bigenic Cdk12 and Trp53 loss allografts represent a new syngeneic model for the study of androgen receptor (AR)-positive, luminal prostate cancer. Notably, Cdk12/Trp53 loss prostate tumors are sensitive to immune checkpoint blockade. Cdk12-null organoids (either with or without Trp53 co-ablation) and patient-derived xenografts from tumors with CDK12 inactivation are highly sensitive to inhibition or degradation of its paralog kinase, CDK13. Together, these data identify CDK12 as a bona fide tumor suppressor gene with impact on tumor progression and lends support to paralog-based synthetic lethality as a promising strategy for treating CDK12-mutant mCRPC.
RESUMEN
Nkx3.1 is a homeoprotein transcription factor (TF) that inhibits proliferation of prostate epithelial cells (PECs) and acts as a tumor suppressor for prostate cancer (PCa). Because TFs classically function within the cells that produce them, Nkx3.1-induced growth inhibition was considered to occur in a cell-autonomous manner. We, however, found that Nkx3.1 protein can be secreted from cultured PECs and is detectable in the prostatic fluid and urine. A PCa-related point mutation (T164A) abolished Nkx3.1 secretion. Amazingly, secreted Nkx3.1 protein can translocate into adjacent cells, bind to the regulatory sequence of Nkx3.1 target genes and impact the expression of these genes in these adjacent cells. Expression of Nkx3.1 in PECs can also affect gene expression in adjacent cells, and this effect is abolished by the T164A mutation. Nkx3.1 protein inhibits cell proliferation when added to the culture. Expression of Nkx3.1, not the T164A mutant, also inhibits the proliferation of co-cultured cells. These results indicate that Nkx3.1 functions as a "para-transcription factor (PTF)," with the ability to regulate genes and inhibit cell proliferation in a non-cell autonomous manner. We also demonstrate that Nkx3.1 contains an evolutionarily conserved protein transduction domain essential for its PTF function, implicating potentially common PTF function among homeoproteins. In addition to the PCa-related T164A mutant, the secreted Nkx3.1 is reduced drastically in the prostatic fluid and urine of mice with PCa. These results indicate that Nkx3.1 can function as a PTF to suppress PCa and the urinary Nkx3.1 may be a potential biomarker for PCa diagnosis.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Proliferación Celular , Células Epiteliales/metabolismo , Proteínas de Homeodominio/metabolismo , Comunicación Paracrina , Próstata/metabolismo , Neoplasias de la Próstata/metabolismo , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Sustitución de Aminoácidos , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/orina , Línea Celular , Células Epiteliales/patología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/orina , Humanos , Masculino , Ratones , Mutación Missense , Próstata/patología , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Estructura Terciaria de Proteína , Transporte de Proteínas/genética , Factores de Transcripción/genética , Factores de Transcripción/orina , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/orinaRESUMEN
Steroid receptor coactivator-1 (SRC-1) is a coactivator for nuclear hormone receptors such as estrogen and progesterone receptors and certain other transcription factors such as Ets-2 and PEA3. SRC-1 expression in breast cancer is associated with HER2 and c-Myc expression and with reduced disease-free survival. In this study, SRC-1(-/-) mice were backcrossed with FVB mice and then cross-bred with MMTV-polyoma middle T antigen (PyMT) mice to investigate the role of SRC-1 in breast cancer. Although mammary tumor initiation and growth were similar in SRC-1(-/-)/PyMT and wild-type (WT)/PyMT mice, genetic ablation of SRC-1 antagonized PyMT-induced restriction of mammary ductal differentiation and elongation. SRC-1(-/-)/PyMT mammary tumors were also more differentiated than WT/PyMT mammary tumors. The intravasation of mammary tumor cells and the frequency and extent of lung metastasis were drastically reduced in SRC-1(-/-)/PyMT mice compared with WT/PyMT mice. Metastatic analysis of transplanted WT/PyMT and SRC-1(-/-)/PyMT tumors in SRC-1(-/-) and WT recipient mice revealed that SRC-1 played an intrinsic role in tumor cell metastasis. Furthermore, SRC-1 was up-regulated during mammary tumor progression. Disruption of SRC-1 inhibited Ets-2-mediated HER2 expression and PyMT-stimulated Akt activation in the mammary tumors. Disruption of SRC-1 also suppressed colony-stimulating factor-1 (CSF-1) expression and reduced macrophage recruitment to the tumor site. These results suggest that SRC-1 specifically promotes metastasis without affecting primary tumor growth. SRC-1 may promote metastasis through mediating Ets-2-mediated HER2 expression and activating CSF-1 expression for macrophage recruitment. Therefore, functional interventions for coactivators like SRC-1 may provide unique approaches to control breast cancer progression and metastasis.
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Neoplasias de la Mama/patología , Regulación Neoplásica de la Expresión Génica , Histona Acetiltransferasas/genética , Metástasis de la Neoplasia/patología , Factores de Transcripción/genética , Animales , Neoplasias de la Mama/etiología , Neoplasias de la Mama/genética , Diferenciación Celular , Femenino , Factor Estimulante de Colonias de Macrófagos/genética , Ratones , Ratones Noqueados , Metástasis de la Neoplasia/genética , Trasplante de Neoplasias , Coactivador 1 de Receptor Nuclear , Proteína Proto-Oncogénica c-ets-2/genética , Receptor ErbB-2/genéticaRESUMEN
Selective degradation of the cyclin-dependent kinases 12 and 13 (CDK12/13) presents a novel therapeutic opportunity for triple-negative breast cancer (TNBC), but there is still a lack of dual CDK12/13 degraders. Here, we report the discovery of the first series of highly potent and selective dual CDK12/13 degraders by employing the proteolysis-targeting chimera (PROTAC) technology. The optimal compound 7f effectively degraded CDK12 and CDK13 with DC50 values of 2.2 and 2.1 nM, respectively, in MDA-MB-231 breast cancer cells. Global proteomic profiling demonstrated the target selectivity of 7f. In vitro, 7f suppressed expression of core DNA damage response (DDR) genes in a time- and dose-dependent manner. Further, 7f markedly inhibited proliferation of multiple TNBC cell lines including MFM223, with an IC50 value of 47 nM. Importantly, 7f displayed a significantly improved antiproliferative activity compared to the structurally similar inhibitor 4, suggesting the potential advantage of a CDK12/13 degrader for TNBC targeted therapy.
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Proteína Quinasa CDC2 , Quinasas Ciclina-Dependientes , Neoplasias de la Mama Triple Negativas , Humanos , Proteína Quinasa CDC2/antagonistas & inhibidores , Línea Celular Tumoral , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Proteolisis , Proteómica , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
Both KRAS and EGFR are essential mediators of pancreatic cancer development and interact with Argonaute 2 (AGO2) to perturb its function. Here, in a mouse model of mutant KRAS-driven pancreatic cancer, loss of AGO2 allows precursor lesion (PanIN) formation yet prevents progression to pancreatic ductal adenocarcinoma (PDAC). Precursor lesions with AGO2 ablation undergo oncogene-induced senescence with altered microRNA expression and EGFR/RAS signaling, bypassed by loss of p53. In mouse and human pancreatic tissues, PDAC progression is associated with increased plasma membrane localization of RAS/AGO2. Furthermore, phosphorylation of AGO2Y393 disrupts both the wild-type and oncogenic KRAS-AGO2 interaction, albeit under different conditions. ARS-1620 (G12C-specific inhibitor) disrupts the KRASG12C-AGO2 interaction, suggesting that the interaction is targetable. Altogether, our study supports a biphasic model of pancreatic cancer development: an AGO2-independent early phase of PanIN formation reliant on EGFR-RAS signaling, and an AGO2-dependent phase wherein the mutant KRAS-AGO2 interaction is critical for PDAC progression.
Asunto(s)
Proteínas Argonautas/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Alelos , Animales , Línea Celular Tumoral , Membrana Celular/metabolismo , Senescencia Celular , Progresión de la Enfermedad , Receptores ErbB/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Genotipo , Humanos , Masculino , Ratones , Ratones Transgénicos , Trasplante de Neoplasias , Neoplasias Pancreáticas/patología , Fosforilación , Unión Proteica , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Although the amplified-in-breast cancer 1 (AIB1; SRC-3, ACTR, or NCoA3) was defined as a coactivator for androgen receptor (AR) by in vitro studies, its role in AR-mediated prostate development and prostate cancer remained unexplored. We report here that AIB1 is expressed in the basal and stromal cells but not in the epithelial cells of the normal mouse prostates. AIB1 deficiency only slightly delayed prostate growth and had no effect on androgen-dependent prostate regeneration, suggesting an unessential role of AIB1 in AR function in the prostate. Surprisingly, when prostate tumorigenesis was induced by the SV40 transgene in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, AIB1 expression was observed in certain epithelial cells of the prostate intraepithelial neoplasia (PIN) and well-differentiated carcinoma and in almost all cells of the poorly differentiated carcinoma. After AIB1 was genetically inactivated in AIB1-/-/TRAMP mice, the progression of prostate tumorigenesis in most AIB1-/-/TRAMP mice was arrested at the well-differentiated carcinoma stage. Wild-type (WT)/TRAMP mice developed progressive, multifocal, and metastatic prostate tumors and died between 25 and 34 weeks. In contrast, AIB1-/-/TRAMP mice only exhibited PIN and early-stage well-differentiated carcinoma by 39 weeks. AIB1-/-/TRAMP prostates showed much lower cell proliferation than WT/TRAMP prostates. Most AIB1-/-/TRAMP mice could survive more than 35 weeks and died with other types of tumors or unknown reasons. Our results indicate that induction of AIB1 expression in partially transformed epithelial cells is essential for progression of prostate tumorigenesis into poorly differentiated carcinoma. Inhibition of AIB1 expression or function in the prostate epithelium may be a potential strategy to suppress prostate cancer initiation and progression.
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Transformación Celular Neoplásica/metabolismo , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Transactivadores/genética , Transactivadores/metabolismo , Animales , Progresión de la Enfermedad , Immunoblotting , Inmunohistoquímica , Hibridación in Situ , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Coactivador 3 de Receptor Nuclear , Próstata/crecimiento & desarrollo , Próstata/metabolismo , Receptores Androgénicos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Transcription factors play a key role in the development of diverse cancers, and therapeutically targeting them has remained a challenge. In prostate cancer, the gene encoding the transcription factor ERG is recurrently rearranged and plays a critical role in prostate oncogenesis. Here, we identified a series of peptides that interact specifically with the DNA binding domain of ERG. ERG inhibitory peptides (EIPs) and derived peptidomimetics bound ERG with high affinity and specificity, leading to proteolytic degradation of the ERG protein. The EIPs attenuated ERG-mediated transcription, chromatin recruitment, protein-protein interactions, cell invasion and proliferation, and tumor growth. Thus, peptidomimetic targeting of transcription factor fusion products may provide a promising therapeutic strategy for prostate cancer as well as other malignancies.
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Antineoplásicos/farmacología , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Peptidomiméticos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Antineoplásicos/química , Línea Celular Tumoral , Embrión de Pollo , ADN/metabolismo , Humanos , Masculino , Ratones Desnudos , Neovascularización Fisiológica/efectos de los fármacos , Proteínas de Fusión Oncogénica/genética , Biblioteca de Péptidos , Peptidomiméticos/química , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Dominios Proteicos , Regulador Transcripcional ERG/antagonistas & inhibidores , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Kdm3b is a JmjC domain-containing histone H3 (H3) demethylase and its physiological functions are largely unknown. In this study, we found that Kdm3b protein is highly expressed in multiple cell types in the mouse testes, including Leydig cells, Sertoli cells, spermatogonia and spermatocytes at different differentiation stages. We also observed Kdm3b protein in the epithelial cells of the caput epididymis, prostate and seminal vesicle. Breeding tests revealed that the number of pups produced by the breeding pairs with Kdm3b knockout (Kdm3bKO) males and wild type (WT) females was reduced 68% because of the decreased number of litters when compared with the breeding pairs with WT males and females. Further analysis demonstrated that Kdm3bKO male mice produced 44% fewer number of mature sperm in their cauda epididymides, displaying significantly reduced sperm motility. No significant differences in the circulating concentration of testosterone and the expression levels of androgen receptor and its representative target genes in the testis were observed. However, the circulating levels of 17ß-estradiol, a modulator of sperm maturation and male sexual behaviors, was markedly reduced in Kdm3bKO male mice. Strikingly, abrogation of Kdm3b in male mice significantly increased the latencies to mount, intromit and ejaculate and decreased the number of mounts and intromissions, largely due to their loss of interest in female odors. These findings indicate that Kdm3b is required for normal spermatogenesis and sexual behaviors in male mice.
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Histona Demetilasas con Dominio de Jumonji/fisiología , Conducta Sexual Animal , Espermatogénesis/genética , Animales , Femenino , Histona Demetilasas con Dominio de Jumonji/genética , Masculino , Ratones , Ratones NoqueadosRESUMEN
Neuroendocrine tumor cells (NETCs) are commonly observed in prostate cancer. Their presence is associated with castration resistance, metastasis and poor prognosis. Cellular and molecular mechanisms for NETC initiation and growth are unknown. TRAMP mice develop heterogeneous adenocarcinomas induced by expression of the SV40-T/t oncogene in prostate epithelial cells. Here, we demonstrate prostate tumors in TRAMP mice with a mixed genetic background are characterized mostly by atypical hyperplasia (AH) containing steroid receptor coactiator-3-positive, androgen receptor-positive and synaptophysin-negative (SRC-3+/AR+/Syp-) cells. Few SRC-3+/AR-/Syp+ NETCs are present in their prostates. We generated TRAMP mice in which SRC-3 was specifically ablated in AR+/Syp- prostatic epithelial cells (termed PE3KOT mice). In these animals, we observed a substantial reduction in SRC-3-/AR+/Syp- AH tumor growth. There was a corresponding increase in SRC-3-/AR+/Syp- phyllodes lesions, suggesting SRC-3 knockout can convert aggressive AH tumors with mostly epithelial tumor cells into less aggressive phyllodes lesions with mostly stromal tissue. Surprisingly, PE3KOT mice developed many more SRC-3+/AR-/Syp+ NETCs versus control TRAMP mice, indicating SRC-3 expression was retained in NETCs. In contrast, TRAMP mice with global SRC-3 knockout did not develop any NETC, indicating SRC-3 is required for developing NETC. Analysis of cell-differentiating markers revealed that these NETCs might not be derived from the mature AR-/Syp+ neuroendocrine cells or the AR+/Syp- luminal epithelial tumor cells. Instead, these NETCs might originate from the SV40-T/t-transformed intermediate/progenitor epithelial cells. In summary, SRC-3 is required for both AR+/Syp- AH tumor growth and AR-/Syp+ NETC development, suggesting SRC-3 is a target for inhibiting aggressive prostate cancer containing NETCs.
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Tumores Neuroendocrinos/metabolismo , Coactivador 3 de Receptor Nuclear/metabolismo , Neoplasias de la Próstata/metabolismo , Animales , Técnicas de Inactivación de Genes , Técnicas Histológicas , Inmunohistoquímica , Masculino , Ratones , Coactivador 3 de Receptor Nuclear/genética , Sinaptofisina/metabolismoRESUMEN
INTRODUCTION: Steroid receptor coactivator-3 (SRC-3), also called amplified-in-breast cancer-1 (AIB1), is an oncogenic coactivator in endocrine and non-endocrine cancers. Functional studies demonstrate SRC-3 promotes numerous aspects of cancer, through its capacity as a coactivator for nuclear hormone receptors and other transcription factors, and via its ability to control multiple growth pathways simultaneously. Targeting SRC-3 with specific inhibitors therefore holds future promise for clinical cancer therapy. AREAS COVERED: We discuss critical advances in understanding SRC-3 as a cancer mediator and prospective drug target. We review SRC-3 structure and function and its role in distinct aspects of cancer. In addition, we discuss SRC-3 regulation and degradation. Finally, we comment on a recently discovered SRC-3 small molecular inhibitor. EXPERT OPINION: Most targeted chemotherapeutic drugs block only a single cellular pathway. In response, cancers frequently acquire resistance by upregulating alternative pathways. SRC-3 coordinates multiple signaling networks, suggesting SRC-3 inhibition offers a promising therapeutic strategy. Development of an effective SRC-3 inhibitor faces critical challenges. Better understanding of SRC-3 function and interacting partners, in both the nucleus and cytosol, is required for optimized inhibitor development. Ultimately, blockade of SRC-3 oncogenic function may inhibit multiple cancer-related signaling pathways.
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Neoplasias/metabolismo , Coactivador 3 de Receptor Nuclear/fisiología , Animales , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
In 1995, the steroid receptor coactivator-1 (SRC-1) was identified as the first authentic steroid receptor coactivator. Since then, the SRC proteins have remained at the epicenter of coregulator biology, molecular endocrinology and endocrine-related cancer. Cumulative works on SRC-1 have shown that it is primarily a nuclear receptor coregulator and functions to construct highly specific enzymatic protein complexes which can execute efficient and successful transcriptional activation of designated target genes. The versatile nature of SRC-1 enables it to respond to steroid dependent and steroid independent stimulation, allowing it to bind across many families of transcription factors to orchestrate and regulate complex physiological reactions. This review highlights the multiple functions of SRC-1 in the development and maintenance of normal tissue functions as well as its major role in mediating hormone receptor responsiveness. Insights from genetically manipulated mouse models and clinical data suggest SRC-1 is significantly overexpressed in many cancers, in particular, cancers of the reproductive tissues. SRC-1 has been associated with cellular proliferation and tumor growth but its major tumorigenic contributions are promotion and execution of breast cancer metastasis and mediation of resistance to endocrine therapies. The ability of SRC-1 to coordinate multiple signaling pathways makes it an important player in tumor cells' escape of targeted therapy.
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Neoplasias/metabolismo , Coactivador 1 de Receptor Nuclear/metabolismo , Animales , Humanos , Neoplasias/genética , Coactivador 1 de Receptor Nuclear/genética , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismoRESUMEN
The androgen and androgen receptor (AR)-regulated gene expression plays important roles in normal prostate and prostate cancer development, and AR transcriptional control of genes is mediated by transcriptional coactivators, including the three members of the steroid receptor coactivator (SRC) family, SRC-1 (NCOA1), SRC-2 (TIF2/GRIP1/NCOA2) and SRC-3 (AIB1, ACTR/RAC3/NCOA3). SRC-1 and SRC-3 are overexpressed in multiple human endocrine cancers and knockdown of either one of them in prostate cancer cell lines impedes cellular proliferation. Knockout of SRC-3 in mice suppresses the progression of spontaneous prostate carcinogenesis. In this study, we investigated SRC-1 contribution to prostate cancer in vivo by deleting the SRC-1 gene in TRAMP mice, which contain the probasin promoter-driven SV40 T/t antigen transgene. In assessing tumor mass of mice at various ages, we found that initiation and progression of prostate cancer induced by SV40 T/t antigens were unaltered in SRC-1(-/-) mice versus WT mice. Primary tumor histology and metastasis to distant lymph nodes were also similar in these mice at all time points assessed. These results demonstrate that the role of SRC-1 in mouse prostate carcinogenesis is nonessential and different from the essential contribution of SRC-3 that is required for prostate cancer progression and metastasis in mice. Interestingly, we observed that during prostate tumorigenesis SRC-1 expression was relatively constant, while SRC-3 expression was significantly elevated. Therefore, the loss of SRC-1 function may be compensated by SRC-3 overexpression during prostate tumorigenesis in SRC-1(-/-) mice.