According to the classification presented by Lehmann BD(2016),triple-negative breast cancer(TNBC)is a heterogeneous group of malignant tumors with four specific subtypes:basal-like(subtype 1 and subtype 2),mesenchymal...According to the classification presented by Lehmann BD(2016),triple-negative breast cancer(TNBC)is a heterogeneous group of malignant tumors with four specific subtypes:basal-like(subtype 1 and subtype 2),mesenchymal,and luminal androgen receptor(LAR)subtypes.The basal-like subtypes of carcinomas predominate in this group,accounting for up to 80%of all cases.Despite the significantly lower proportions of mesenchymal and LAR variants in the group of breast carcinomas with a TNBC profile,such tumors are characterized by aggressive biological behavior.To this end,the LAR subtype is of particular interest,since the literature on such tumors presents different and even contradictory data concerning the disease course and prognosis.This review is devoted to the analysis of the relevant literature,reflecting the main results of studies on the molecular properties and clinical features of the disease course of LAR-type TNBC carcinomas.展开更多
A complete proteomics study characterizing active androgen receptor(AR)complexes in prostate cancer(PCa)cells identified a diversity of protein interactors with tumorigenic annotations,including known RNA splicing fac...A complete proteomics study characterizing active androgen receptor(AR)complexes in prostate cancer(PCa)cells identified a diversity of protein interactors with tumorigenic annotations,including known RNA splicing factors.Thus,we chose to further investigate the functional role of AR-mediated alternative RNA splicing in PCa disease progression.We selected two AR-interacting RNA splicing factors,Src associated in mitosis of 68 kDa(SAM68)and DEAD(Asp-Glu-Ala-Asp)box helicase 5(DDX5)to examine their associative roles in AR-dependent alternative RNA splicing.To assess the true physiological role of AR in alternative RNA splicing,we assessed splicing profiles of LNCaP PCa cells using exon microarrays and correlated the results to PCa clinical datasets.As a result,we were able to highlight alternative splicing events of clinical significance.Initial use of exon-mini gene cassettes illustrated hormone-dependent AR-mediated exon-inclusion splicing events with SAM68 or exon-exclusion splicing events with DDX5 overexpression.The physiological significance in PCa was investigated through the application of clinical exon array analysis,where we identified exon-gene sets that were able to delineate aggressive disease progression profiles and predict patient disease-free outcomes independently of pathological clinical criteria.Using a clinical dataset with patients categorized as prostate cancer-specific death(PCSD),these exon gene sets further identified a select group of patients with extremely poor disease-free outcomes.Overall,these results strongly suggest a nonclassical role of AR in mediating robust alternative RNA splicing in PCa.Moreover,AR-mediated alternative spicing contributes to aggressive PCa progression,where we identified a new subtype of lethal PCa defined by AR-dependent alternative splicing.展开更多
Triple negative breast cancer(TN BC)is a complex and malignant breast cancer subtype that lacks expression of the estrogen receptor(ER),progesterone receptor(PR)and human epidermal growth factor receptor 2(H ER2),ther...Triple negative breast cancer(TN BC)is a complex and malignant breast cancer subtype that lacks expression of the estrogen receptor(ER),progesterone receptor(PR)and human epidermal growth factor receptor 2(H ER2),thereby making therapeutic targeting difficult.TNBC is generally considered to have high malignancy and poor prognosis.However,patients diagnosed with certain rare histomorphologic subtypes of TNBC have better prognosis than those diagnosed with typical triple negative breast cancer.In addition,with the discovery and development of novel treatment targets such as the androgen receptor(AR),PI3K/AKT/mTOR and AMPK signaling pathways,as well as emerging immunotherapies,the therapeutic options for TNBC are increasing.In this paper,we review the literature on various histological types of TNBC and focus on newly developed therapeutic strategies that target and potentially affect molecular pathways or emerging oncogenes,thus providing a basis for future tailored therapies focused on the mutational aspects of TNBC.展开更多
Prostate cancer(PCa)exhibits epidemiological and molecular heterogeneity.Despite extensive studies of its phenotypic and genetic properties in Western populations,its molecular basis is not clear in Chinese patients.T...Prostate cancer(PCa)exhibits epidemiological and molecular heterogeneity.Despite extensive studies of its phenotypic and genetic properties in Western populations,its molecular basis is not clear in Chinese patients.To determine critical molecular characteristics and explore correlations between genomic markers and clinical parameters in Chinese populations,we applied an integrative genetic/transcriptomic assay that combines targeted next-generation sequencing and quantitative real-time PCR(qRT-PCR)on samples from 46 Chinese patients with PCa.Lysine(K)-specific methyltransferase 2D(KMT2D),zinc finger homeobox 3(ZFHX3),A-kinase anchoring protein 9(AKAP9),and GLI family zinc finger 1(GLI1)were frequently mutated in our cohort.Moreover,a clinicopathological analysis showed that RB transcriptional corepressor 1(RB1)deletion was common in patients with a high risk of disease progression.Remarkably,four genomic events,MYC proto-oncogene(MYC)amplification,RB1 deletion,APC regulator of WNT signaling pathway(APC)mutation or deletion,and cyclin-dependent kinase 12(CDK12)mutation,were correlated with poor disease-free survival.In addition,a close link between KMT2D expression and the androgen receptor(AR)signaling pathway was observed both in our cohort and in The Cancer Genome Atlas Prostate Adenocarcinoma(TCGA-PRAD)data.In summary,our results demonstrate the feasibility and benefits of integrative molecular characterization of PCa samples in disease pathology research and personalized medicine.展开更多
文摘According to the classification presented by Lehmann BD(2016),triple-negative breast cancer(TNBC)is a heterogeneous group of malignant tumors with four specific subtypes:basal-like(subtype 1 and subtype 2),mesenchymal,and luminal androgen receptor(LAR)subtypes.The basal-like subtypes of carcinomas predominate in this group,accounting for up to 80%of all cases.Despite the significantly lower proportions of mesenchymal and LAR variants in the group of breast carcinomas with a TNBC profile,such tumors are characterized by aggressive biological behavior.To this end,the LAR subtype is of particular interest,since the literature on such tumors presents different and even contradictory data concerning the disease course and prognosis.This review is devoted to the analysis of the relevant literature,reflecting the main results of studies on the molecular properties and clinical features of the disease course of LAR-type TNBC carcinomas.
基金This work was supported by a research grant from Prostate Cancer Canada#673 to MP.
文摘A complete proteomics study characterizing active androgen receptor(AR)complexes in prostate cancer(PCa)cells identified a diversity of protein interactors with tumorigenic annotations,including known RNA splicing factors.Thus,we chose to further investigate the functional role of AR-mediated alternative RNA splicing in PCa disease progression.We selected two AR-interacting RNA splicing factors,Src associated in mitosis of 68 kDa(SAM68)and DEAD(Asp-Glu-Ala-Asp)box helicase 5(DDX5)to examine their associative roles in AR-dependent alternative RNA splicing.To assess the true physiological role of AR in alternative RNA splicing,we assessed splicing profiles of LNCaP PCa cells using exon microarrays and correlated the results to PCa clinical datasets.As a result,we were able to highlight alternative splicing events of clinical significance.Initial use of exon-mini gene cassettes illustrated hormone-dependent AR-mediated exon-inclusion splicing events with SAM68 or exon-exclusion splicing events with DDX5 overexpression.The physiological significance in PCa was investigated through the application of clinical exon array analysis,where we identified exon-gene sets that were able to delineate aggressive disease progression profiles and predict patient disease-free outcomes independently of pathological clinical criteria.Using a clinical dataset with patients categorized as prostate cancer-specific death(PCSD),these exon gene sets further identified a select group of patients with extremely poor disease-free outcomes.Overall,these results strongly suggest a nonclassical role of AR in mediating robust alternative RNA splicing in PCa.Moreover,AR-mediated alternative spicing contributes to aggressive PCa progression,where we identified a new subtype of lethal PCa defined by AR-dependent alternative splicing.
基金the National Natural Science Foundation of China(Grant No.81172532).
文摘Triple negative breast cancer(TN BC)is a complex and malignant breast cancer subtype that lacks expression of the estrogen receptor(ER),progesterone receptor(PR)and human epidermal growth factor receptor 2(H ER2),thereby making therapeutic targeting difficult.TNBC is generally considered to have high malignancy and poor prognosis.However,patients diagnosed with certain rare histomorphologic subtypes of TNBC have better prognosis than those diagnosed with typical triple negative breast cancer.In addition,with the discovery and development of novel treatment targets such as the androgen receptor(AR),PI3K/AKT/mTOR and AMPK signaling pathways,as well as emerging immunotherapies,the therapeutic options for TNBC are increasing.In this paper,we review the literature on various histological types of TNBC and focus on newly developed therapeutic strategies that target and potentially affect molecular pathways or emerging oncogenes,thus providing a basis for future tailored therapies focused on the mutational aspects of TNBC.
基金This work was mainly supported by the National Key R&D Program of China(No.2017YFC1103403)the National Natural Science Foundation of China(No.21773199,No.61427807 and No.81872092)+1 种基金the Sanming Project of Medicine in Shenzhen(No.SZSM201612019)the PhD Start-up Fund of Natural Science Foundation of Guangdong Province of China(No.2016A030310287).
文摘Prostate cancer(PCa)exhibits epidemiological and molecular heterogeneity.Despite extensive studies of its phenotypic and genetic properties in Western populations,its molecular basis is not clear in Chinese patients.To determine critical molecular characteristics and explore correlations between genomic markers and clinical parameters in Chinese populations,we applied an integrative genetic/transcriptomic assay that combines targeted next-generation sequencing and quantitative real-time PCR(qRT-PCR)on samples from 46 Chinese patients with PCa.Lysine(K)-specific methyltransferase 2D(KMT2D),zinc finger homeobox 3(ZFHX3),A-kinase anchoring protein 9(AKAP9),and GLI family zinc finger 1(GLI1)were frequently mutated in our cohort.Moreover,a clinicopathological analysis showed that RB transcriptional corepressor 1(RB1)deletion was common in patients with a high risk of disease progression.Remarkably,four genomic events,MYC proto-oncogene(MYC)amplification,RB1 deletion,APC regulator of WNT signaling pathway(APC)mutation or deletion,and cyclin-dependent kinase 12(CDK12)mutation,were correlated with poor disease-free survival.In addition,a close link between KMT2D expression and the androgen receptor(AR)signaling pathway was observed both in our cohort and in The Cancer Genome Atlas Prostate Adenocarcinoma(TCGA-PRAD)data.In summary,our results demonstrate the feasibility and benefits of integrative molecular characterization of PCa samples in disease pathology research and personalized medicine.
