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.