Role of YB1 in health disparities in triple negative breast cancer
Role of YB1 in health disparities in triple negative breast cancer
批准号:
10655943
负责人:
KHALID SOSSEY-ALAOUI
金额:
$48.16万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-05-12 至 2028-04-30
关键词:
AddressAffectAfrican AmericanAgeAnimalsAreaBehaviorBiologicalBiological MarkersBreast Cancer PatientBreast Cancer cell lineBreast DiseasesCancer Death RatesChemoresistanceClinicalCombined Modality TherapyComplexDataData SetDeath RateDiagnosisDiseaseDisease OutcomeDisparityDisparity populationEnvironmentEthnic PopulationFormalinGeneral PopulationGenesGeneticGoalsHospitalsHumanImmunohistochemistryIn VitroIncidenceInvadedLife StyleMalignant NeoplasmsMalignant neoplasm of ovaryMediatingMedical centerModalityMolecularNeoadjuvant TherapyNeoplasm MetastasisNuclearOhioOncogenicOutcomeParaffin EmbeddingPathologicPatientsPhenotypePhosphorylationPlayPopulationPrimary NeoplasmPrognosisPublishingRaceRecurrenceResistanceRoleSerineSignal PathwaySignal TransductionSiteSocioeconomic StatusTestingTherapeuticTissue EmbeddingTumor BiologyTumorigenicityVariantVulnerable PopulationsWomanXenograft procedureblack womencancer health disparitycancer stem cellcaucasian Americanchemotherapyclinically significantcohortdifferential expressioneffectiveness evaluationgenetic manipulationhealth disparityhealth equityimprovedin vivoinnovationmalignant breast neoplasmneoplastic cellnoveloutcome disparitiespopulation basedpotential biomarkerpredicting responsepredictive markerprogression markerpublic health relevanceracial disparityracial populationresponseresponse biomarkersmall moleculesociodemographic factorssocioeconomicsstandard of caresuccesstargeted treatmenttherapeutic targettherapy resistanttranscriptomicstriple-negative invasive breast carcinomatumor
中文摘要
项目摘要
三阴性乳腺癌(TNBC)的侵袭性部分是由于它们的转移性肿瘤。
行为、快速复发倾向和对标准治疗的低反应
化疗TNBC与最差的预后和临床结果相关,
尤其是在非洲裔美国人(AA)妇女中。有趣的是,TNBC的发病率更高,
AA女性中,与他们的白人美国人(CA)相比,
有同样的疾病。这些与种族相关的结果差异,
即使在控制了社会经济和治疗差异后,
表明肿瘤生物学的差异对癌症结果的这些差异的贡献。
我们确定YB 1是一种多功能基因,是TNBC差异的潜在生物驱动因素,
戒酒会的女人。我们还发现YB 1的致癌信号传导可能在激活细胞凋亡中起主要作用。
AA妇女中TNBC的侵袭-转移级联和治疗抗性。yb 1表达
AA肿瘤中的水平显著更高,并且与较差的总体生存率密切相关。
在AA TNBC患者中。YB 1核定位/磷酸化(S102)也与
癌症干细胞表型和AA来源的TNBC肿瘤对化疗的抗性。基于
基于这一强有力的证据,我们提出了YB 1致癌信号传导的总体假设,
是AA和CA TNBC之间疾病结局差异的主要促成因素
患者这一假设将通过研究生物学和临床意义来解决
YB 1信号轴在TNBC差异中的作用。我们的提案还将试图更好地阐明
遗传学、环境、社会经济学和生活方式之间复杂的相互作用,
有助于观察到的差异,最终目标是制定和实施更多的
有效的基于人口的战略,以改善这一弱势群体的健康公平。
我们的具体目标是(1)确定YB 1信号传导(表达,磷酸化和
核定位)在TNBC细胞系和AA肿瘤的致瘤性和化学抗性中的作用
(2)确定靶向YB 1的新型联合治疗对缓解
AA TNBC肿瘤的进展和转移;和(3)确定YB 1信号传导是否可以
根据转录组学预测TNBC的种族差异和化疗耐药性,
免疫组化
我们坚信,我们的创新建议将为该领域做出巨大贡献。
癌症差异,特别是AA女性与TNBC,并将确定新的YB 1为基础的
这种毁灭性的癌症是严重影响AA妇女的治疗选择。
英文摘要
Project Summary
The aggressiveness of triple negative breast cancers (TNBCs) is, in part, due to their metastatic
behavior, propensity to recur rapidly and dismal low response to standard-of-care
chemotherapies. TNBCs are associated with the worst prognosis and clinical outcomes,
especially in African American (AA) women. Interestingly, the incidence rate of TNBC is more
than 2-fold higher in AA women, compared with their Caucasian American (CA) counterparts who
have the same disease. These racial-associated disparities in outcomes, that remain poorly
understood, are significant even after controlling for socioeconomic and treatment variations, and
suggest the contribution of differences in tumor biology to these disparities in cancer outcomes.
We identified YB1, a multifunctional gene, as a potential biological driver of TNBC disparities in
AA women. We also found that the oncogenic signaling of YB1 may play a major role in activating
the invasion-metastasis cascade and therapy resistance of TNBC in AA women. YB1 expression
levels are significantly higher in AA tumors and are strongly associated with poorer overall survival
in AA TNBC patients. YB1 nuclear localization/phosphorylation (S102) is also correlated with
cancer stem cell phenotype, and resistance to chemotherapy in TNBC tumors of AA origin. Based
on this strong evidence, we developed the overarching hypothesis that YB1 oncogenic signaling
is a major contributing factor to differences in disease outcomes between AA and CA TNBC
patients. This hypothesis will be addressed by investigating the biologic and clinical significance
of YB1 signaling axis in TNBC disparities. Our proposal will also attempt to better elucidate the
complex interactions between genetics, environment, socioeconomics and lifestyle that may
contribute to the observed differences with the ultimate goal of developing and implementing more
efficacious population-based strategies to improve health equity for this vulnerable population.
Our specific aims will (1) Determine the impact of YB1 signaling (expression, phosphorylation and
nuclear localization) in tumorigenicity and chemoresistance in TNBC cell lines and tumors of AA
origin; (2) Determine the impact of novel combination therapies targeting YB1 to alleviate
progression and metastasis of AA TNBC tumors; and (3) Determine whether YB1 signaling can
predict racial disparities and chemoresistance in TNBC, based on transcriptomics and
immunohistochemistry.
We are very confident that our innovative proposal will make great contributions to the field of
cancer disparities, especially for AA women with TNBC, and will identify new YB1-based
therapeutic options for this devastating cancer that is disparately affecting AA women.
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专著(0)
科研奖励(0)
会议论文
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依托单位:
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依托单位:
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