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