Americans of Hispanic and African heritage are at higher risk to develop molecular subtypes of breast cancer that associate with poor prognosis, including triple-negative (ER-PR-Her2-) and Her2+ breast cancers relative to Non-Hispanic whites. Increased chromosome instability (CI) in most cancers correlates with poor clinical outcomes and higher levels of CI is observed in poor-prognosis HR- breast cancers relative to luminal subtypes. Centrosome amplification, or the accumulation of 3 or more centrosomes within a cell, and defective mitosis are two principal drivers of chromosome instability. Centrosome amplification correlates with invasion, metastasis, poor clinical outcomes, and HR- subtypes. Interestingly, we identified TTK and TBK1 kinases as regulators of centrosome amplification in cancer cells. TTK and TBK1 are centrosome/mitotic regulators, and reports indicate TBK1 can regulate mitotic progression directly, and indirectly through phosphorylation of Plk1, which phosphorylates TTK to modulate the spindle assembly checkpoint. Our preliminary data show that these two mitotic kinases can significantly influence epithelial to mesenchymal transition (EMT), an activity never described for mitotic kinases. Silencing of TTK reduces phosphorylation of SMAD3 upon TGF- stimulation, suppressing regulators of EMT. In a similar fashion, recent studies from the Chellappan lab identified TBK1 physically interacts with the E2F1 transcription factor, which induces the expression of TTK, and EMT genes like vimentin, fibronectin, ZEB-1, and ZEB2. Further, depletion of TBK1 could significantly reduce the expression of MMP2 and MMP9, suggesting that kinases involved in mitosis like TTK and TBK1 can contribute significantly to the EMT and metastasis of tumors. Chemical inhibition of TTK and TBK1 reduced levels of EMT regulators (Slug, SNAIL), as well as important regulators of the centrosome cycle and mitosis (p-H3, cyclin B, Aurora kinase A). Since inhibitors are available for TTK and TBK1, it would be feasible to target these kinases to combat HR- breast cancers. We hypothesize that elevated levels and activity of TTK and TBK1 enhance tumor growth, epithelial to mesenchymal transition (EMT) and metastasis, and that such events correlate with prognostic molecular subtypes and survival outcomes of H/L breast cancer patients from Puerto Rico. To test this hypothesis, we propose the following Aims: 1. To establish if TTK and TBK1 contribute to poor prognosis molecular subtypes and surrogate markers of survival in Hispanics/Latinos. 2. To determine how TTK and TBK1 drive the epithelial-to-mesenchymal transition and promote invasion. 3. To determine how TTK and TBK1 impact tumor growth and metastasis. Data resulting from the proposed experiments will allow the identification of pathways influenced by mitotic regulators in breast cancer cells driving invasion and metastasis, and will provide potential prognostic markers for high-risk breast tumors in Hispanics/Latinos.
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