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（US）的非西班牙裔黑人（NHB）和西班牙裔/拉丁裔（H/L）女性 非西班牙裔白色（NHW）女性的乳腺癌相关死亡率。来自加勒比的H/L妇女（C-H/L， 波多黎各人、古巴人和多米尼加人）和黑人H/L的死亡风险甚至高于来自其他种族的H/L。 区域和白色H/L。这种更高的风险部分是由于NHB和C-H/L与乳腺癌更有可能 在更年轻的年龄，更高阶段和级别的肿瘤以及三阴性乳腺癌中被检测到 （ER-PR-和Her 2-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女性的这些风险因素（平均有79%和27%的非洲基因组 的贡献）。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）和非整倍体也可能导致这些TNBC的转移和不良临床结局 患者Co-PI发表了中心体/有丝分裂激酶TTK、NEK 2和TBK 1产生CA/CIN TTK和NEK 2驱动上皮细胞向间质细胞转化（EMT）。初步数据显示， TTK、NEK 2和TBK 1 mRNA在NHB和TNBC中失调，并在乳腺肿瘤中过表达 C/H/L。此外，通过使用新的NCI-BMAP 3区域乳腺癌组织微阵列（TMA）， 从NHW、NHB和C-H/L妇女的样本中，Co-PI发现TTK和pTBK 1在TNBC中过表达， TTK与TNBC中的EMT相关。在TNBC细胞中，TTK或TBK 1失活可恢复Rb，这表明它可以 恢复Palbociclib反应。TNBC细胞中的TTK和TBK 1共失活降低了TNBC细胞中TTK和TBK 1的水平。 中心体/有丝分裂调节因子和EMT标记物，并显著共失活TTK/TBK 1或TTK/NEK 2 减少了TNBC的迁移和侵袭。研究小组假设TTK、NEK 2和TBK 1 C-H/L和NHB女性乳腺癌（BC）的失调是由非洲血统决定的， 通过推动癌细胞生存和早期转移来减少其不良生存结果。为了验证这一假设， 研究小组提出了以下具体目标：（1）研究有丝分裂激酶与早期 非西班牙裔黑人（NHB）、加勒比西班牙裔/拉丁裔（C-H/L）的转移和预后不良， 患有乳腺癌的西班牙裔/拉丁裔（H/L）女性。研究小组将确定RNA表达签名和复制是否 数量变化与有丝分裂激酶的表达和EMT标记，以及生存结果相关， 使用ORIEN财团完成的RNA和DNA测序以及波多黎各开发的新型TMA， 生物银行(2)为了解决有丝分裂激酶的共失活如何抑制间充质状态，转移， 并恢复TNBC细胞中的Palbociclib应答。这将通过单一和组合抑制来解决 TTK、NEK 2和TBK 1在来自患有乳腺癌的NHB和H/L女性的TNBC的原代细胞系和PDX模型中的表达 癌拟议实验的结果将有助于减少种族/种族乳腺癌的差异， 鉴定针对侵袭性细胞的可作用靶点（TTK、NEK 2、TBK 1和在Aim 1中发现的其他新型激酶）。 在患有TNBC的NHB和H/L女性中的生长和早期转移进展。