Targeting centrosome‐mitotic kinases as a novel therapeutic approach against breast cancers in Hispanic/Latinas.

靶向中心体有丝分裂激酶作为治疗西班牙裔/拉丁裔乳腺癌的新方法。

• 批准号: 10539820
• 负责人: William Douglas Cress
• 金额: $ 48.32万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539820
• 关键词: Address; African; African Caribbean; African ancestry; Age; Aggressive behavior; Aneuploidy; Automobile Driving; Biological Markers; Biological Response Modifier Therapy; Black Populations; Black race; Breast Cancer Patient; Cancer Center; Caribbean Hispanic; Caribbean region; Cell Line; Cell Survival; Cells; Centrosome; Cessation of life; Chromosomal Instability; Chromosomes; Clinical; Copy Number Polymorphism; Cuban; DNA sequencing; Data; Diagnosis; Dominican; E-Cadherin; Estrogens; Ethnic Origin; European; Functional disorder; Gene Expression Profile; Generations; Genetic Transcription; Genome; Genomics; Goals; Growth; Hispanic; Incidence; Individual; Laboratories; Latina Population; Latino; Link; Malignant Neoplasms; Mammary Neoplasms; Measures; Mesenchymal; Messenger RNA; Mitotic; Molecular; Nature; Neoplasm Metastasis; Not Hispanic or Latino; Organoids; Outcome; Pathology; Pathway interactions; Patient-derived xenograft models of breast cancer; Patients; Phosphorylation; Phosphotransferases; Prevalence; Principal Investigator; Probability; Progesterone; Prognosis; Publishing; Puerto Rican; Puerto Rico; Race; Relapse; Research Personnel; Risk Factors; Sampling; Signal Pathway; Socioeconomic Status; Survival Rate; TBK1 gene; Testing; The Cancer Genome Atlas; Tissue Microarray; Transitional Cell; Treatment outcome; Tumor Markers; Tumor stage; United States; Vimentin; Woman; aurora kinase; biobank; black women; breast cancer survival; cancer cell; cancer health disparity; combinatorial; epithelial to mesenchymal transition; experimental study; high risk; improved; inhibitor; malignant breast neoplasm; migration; mortality risk; novel; novel therapeutic intervention; overexpression; patient derived xenograft model; prevent; racial and ethnic; racial and ethnic disparities; receptor; recruit; response; slug; stemness; survival outcome; transcription factor; transcriptome sequencing; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor heterogeneity; tumor initiation; whole genome

Non-Hispanic black (NHB) and Hispanic/Latino (H/L) women in the United States (US) have higher probabilities of breast cancer-related death than non-Hispanic white (NHW) women. H/L women from the Caribbean (C-H/L, Puerto Rican, Cuban and Dominican) and black H/L are at an even higher risk of death than H/L from other regions and white H/L. This higher risk is in part due to NHB and C-H/L with breast cancers being more likely to be detected at younger ages, with tumors of higher stages and grades, and with triple-negative breast cancers (ER-PR- and Her2- or TNBC). African ancestry combined with less of the protective European genome greatly influences these risk factors in NHB and C-H/L women (on average having 79% and 27% African genomic contribution, respectively). Centrosome amplification-driven mitotic dysfunction leading to chromosome instability (CIN) and aneuploidy may also contribute to metastasis and poor clinical outcomes of these TNBC patients. The Co-PIs published that the centrosome/mitotic kinases TTK, NEK2, and TBK1 generate CA/CIN and that TTK and NEK2 drive the epithelial to mesenchymal transition (EMT). Preliminary data indicates that TTK, NEK2, and TBK1 mRNAs are dysregulated in NHB and TNBCs, and are overexpressed in breast tumors from C-H/L. Also, by using a novel NCI-BMAP3 region breast cancer tissue microarray (TMA) containing samples from NHW, NHB, and C-H/L women, the Co-PIs found that TTK and pTBK1 are overexpressed in TNBC and TTK correlates with EMT in TNBC. Inactivating TTK or TBK1 restored Rb in TNBC cells, suggesting it can restore Palbociclib responses. Co-inactivating TTK and TBK1 in TNBC cells reduced the levels of centrosome/mitotic regulators and EMT markers, and co-inactivating TTK/TBK1 or TTK/NEK2 significantly reduced the migration and invasion of TNBC. The study team hypothesizes that TTK, NEK2, and TBK1 dysregulation in C-H/L and NHB women with breast cancer (BC) is dictated by African ancestry and contributes to their poor survival outcomes by driving cancer cell survival and early metastasis. To test this hypothesis, the team proposes the following Specific Aims: (1) Investigating signaling pathways linking mitotic kinases to early metastasis and poor prognosis of non-Hispanic black (NHB), Caribbean Hispanic/Latino (C-H/L), and Hispanic/Latino (H/L) women with breast cancer. The team will determine if RNA expression signatures and copy number variations correlate with the expression of mitotic kinases with EMT markers, and survival outcomes, using RNA and DNA seq done by the ORIEN consortium and a novel TMA developed by the Puerto Rico Biobank. (2) To address how co-inactivation of mitotic kinases suppresses the mesenchymal state, metastasis, and restores Palbociclib responses in TNBC cells. This will be addressed by single and combinatorial inhibition of TTK, NEK2, and TBK1 in primary cell lines and PDX models of TNBC from NHB and H/L women with breast cancer. Results from the proposed experiments will help reduce ethnic/racial breast cancer disparities by identifying actionable targets (TTK, NEK2, TBK1, and other novel kinases found in Aim 1) against the aggressive growth and early metastatic progression in NHB and H/L women with TNBC.

美国的非西班牙裔黑人（NHB）和西班牙裔/拉丁裔（H/L）妇女（美国）具有更高的概率 与非西班牙裔白人（NHW）女性相比，与乳腺癌相关的死亡的死亡。来自加勒比海的H/L妇女（C-H/L， 波多黎各人，古巴和多米尼加）和黑色H/L的死亡风险比其他H/L更高 区域和白色H/L。这种较高的风险部分是由于NHB和C-H/L乳腺癌更有可能 在年轻人时期检测到具有较高阶段和成绩的肿瘤，并且具有三阴性乳腺癌 （ER-PR-和HER2-或TNBC）。非洲血统与较少的保护性欧洲基因组相结合 影响NHB和C-H/L女性的这些危险因素（平均具有79％和27％的非洲基因组。 分别贡献）。中心体扩增驱动的有丝分裂功能障碍​​导致染色体 不稳定性（CIN）和非整倍性也可能导致这些TNBC的转移和临床不良结果 患者。 Co-Pis发表的表明，中心体/有丝分裂激酶TTK，NEK2和TBK1产生CA/CIN 并且TTK和NEK2驱动上皮到间充质转变（EMT）。初步数据表明 TTK，NEK2和TBK1 mRNA在NHB和TNBC中失调，在乳腺肿瘤中过表达 来自C-H/L。另外，使用新型的NCI-BMAP3区域乳腺癌组织微阵列（TMA），其中包含 来自NHW，NHB和C-H/L女性的样本，Co-Pis发现TTK和PTBK1在TNBC中过表达 TTK与TNBC中的EMT相关。灭活TTK或TBK1在TNBC细胞中恢复了RB，这表明可以 恢复palbociclib的响应。在TNBC细胞中共同吸收TTK和TBK1降低了 中心体/有丝分裂调节剂和EMT标记物，并显着吸收TTK/TBK1或TTK/NEK2 减少了TNBC的迁移和入侵。研究团队假设TTK，NEK2和TBK1 C-H/L和NHB乳腺癌妇女（BC）的失调由非洲血统决定，并有助于 通过驱动癌细胞存活和早期转移来使他们的生存结果不佳。为了检验这一假设， 团队提出以下特定目的：（1）调查将有丝分裂激酶与早期联系起来的信号通路 非西班牙裔黑（NHB），加勒比西班牙裔/拉丁裔（C-H/L）的转移和预后不良 西班牙裔/拉丁裔（H/L）患有乳腺癌的妇女。团队将确定RNA表达签名并复制 数量变化与具有EMT标记的有丝分裂激酶的表达以及生存结果相关， 使用Orien财团和波多黎各开发的新型TMA进行的RNA和DNA SEQ 生物库。 （2）解决有丝分裂激酶的共同吸收如何抑制间充质状态的转移， 并恢复TNBC细胞中的palbociclib反应。这将通过单一和组合抑制来解决 来自NHB和H/L乳腺女性的TNBC的TTK，NEK2和TBK1的TTK，NEK2和TBK1 癌症。拟议的实验的结果将有助于减少种族/种族乳腺癌的差异 识别可行的目标（TTK，NEK2，TBK1和AIM中发现的其他新型激酶1）反对侵略性 NHB和H/L女性TNBC的生长和早期转移进展。