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Principal Investigator: William Douglas Cress
Organization: PONCE SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $486,917
Funding agency: National Cancer Institute
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.
Terms: <Address><African><African ancestry><African descent><Age><Aggression><Aggressive behavior><Aneuploid><Aneuploidy><Automobile Driving><Basal Transcription Factor><Basal transcription factor genes><Biological Markers><Biological Response Modifier Therapy><Biological Therapy><Black><Black Populations><Black group><Black individual><Black people><Black race><Blacks><Breast Cancer><Breast Cancer Patient><Breast Neoplasms><Breast PDX models><Breast Tumor Patient><Breast Tumors><Cadherin-1><Cancer Center><Cancers><Caribbean><Caribbean Hispanic><Caribbean Sea Region><Caribbean region><Caucasian Females><Caucasian Women><Cell Body><Cell Line><Cell Survival><Cell Viability><CellLine><Cells><Centrosome><Cessation of life><Chromosomal Instability><Chromosome Instability><Chromosomes><Clinical><Copy Number Polymorphism><Corpus Luteum Hormone><Cuban><DNA seq><DNA sequencing><DNAseq><Data><Death><Delta4-pregnene-3,20-dione><Diagnosis><Disparities><Disparity><Dominican><Dysfunction><E-Cadherin><Epithelial Calcium-Dependent Adhesion Protein><Epithelial-Cadherin><Estrogens><Ethnic Origin><Ethnicity><European><European ancestry><Expression Signature><FLJ11330><Functional disorder><Gene Expression Profile><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Generations><Genetic Transcription><Genome><Genomics><Goals><Growth><Hispanic><Incidence><Individual><Intratumoral heterogeneity><Invaded><Investigators><Kinases><Laboratories><Latina Population><Latinas><Latino><Link><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mammary Cancer><Mammary Neoplasms><Measures><Mesenchymal><Messenger RNA><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mitotic><Molecular><NF-Kb-Activating Kinase Gene><Nature><Neoplasm Metastasis><Non-Hispanic><Nonhispanic><Not Hispanic or Latino><Organoids><Outcome><PDX model><Pathology><Pathway interactions><Patient derived xenograft><Patient-derived xenograft models of breast cancer><Patients><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Physiopathology><Pregn-4-ene-3,20-dione><Pregnenedione><Prevalence><Principal Investigator><Probability><Progesterone><Prognosis><Proliferating><Protein Phosphorylation><Publishing><Puerto Rican><Puerto Rico><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Race><Races><Receptor Protein><Relapse><Research Personnel><Researchers><Risk Factors><Sampling><Secondary Neoplasm><Secondary Tumor><Signal Pathway><Socio-economic status><Socioeconomic Status><Stem Cell like><Strains Cell Lines><Survival Rate><T-Stage><T2K><TBK1><TBK1 gene><TCGA><TM-MKR><TNBC><Testing><The Cancer Genome Atlas><Therapeutic Estrogen><Therapeutic Progesterone><Tissue Arrays><Tissue Chip><Tissue Growth><Tissue Microarray><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transphosphorylases><Treatment outcome><Tumor Markers><Tumor stage><United States><Uvomorulin><Vimentin><West Indies Region><White Females><White Women><Woman><ages><aurora kinase><bio-markers><biobank><biologic marker><biological therapeutic><biological treatment><biologically based therapeutics><biomarker><biorepository><biotherapeutics><biotherapy><black female><black women><breast cancer PDX><breast cancer patient-derived xenograft><breast cancer survival><cancer cell><cancer disparity><cancer health disparity><cancer metastasis><cancer-related health disparity><combinatorial><copy number variant><copy number variation><cultured cell line><death risk><disparities in race><disparity due to race><disparity in cancer><disparity in ethnic><driving><entire genome><epithelial to mesenchymal transition><ethnic based disparity><ethnic disadvantage><ethnic disparity><ethnic inequality><ethnic inequity><ethnicity disparity><experiment><experimental research><experimental study><experiments><full genome><gene expression pattern><gene expression signature><heterogeneity in tumors><high risk><improved><inequality due to race><inequity due to race><inhibitor><intra-tumoral heterogeneity><intratumor heterogeneity><mRNA><malignancy><malignant breast tumor><mammary tumor><migration><mortality risk><neoplasm/cancer><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><ontogeny><overexpress><overexpression><pathophysiology><pathway><patient derived xenograft model><prevent><preventing><race based disparity><race based inequality><race based inequity><race disparity><race related disparity><race related inequality><race related inequity><racial><racial background><racial disparity><racial diversity><racial inequality><racial inequity><racial origin><racially diverse><racially unequal><receptor><recruit><response><slug><socio-economic position><socioeconomic position><stem cell characteristics><stemness><survival outcome><transcription factor><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor biomarker><tumor cell metastasis><tumor growth><tumor heterogeneity><tumor initiation><tumor specific biomarker><whole genome>