Targeting centrosome-mitotic kinases as a novel therapeutic approach against breast cancers in Hispanic/Latinas. Supplement1 - Project Summary
Non-Hispanic Black (NHB) and Hispanic/Latino (H/L) women with breast cancer have elevated mortality
rates relative to non-Hispanic White (NHW) women with breast cancer. This is, in part, due to the detection of
breast tumors at higher stages, and because of higher rates of triple-negative breast cancer (TNBC), a highly
aggressive breast cancer subtype associated with poor prognosis because of the lack of Estrogen (E),
Progesterone (P), and Her2 receptors. The prevalence of African ancestry in the genome of H/L from the
Caribbean (C-H/L) and NHB may contribute to elevated mortality rates because of higher rates of TNBC in
C-H/L and NHB relative to H/L and NHW women. Therefore, there is a need to identify novel biological
therapies specific to women of African heritage with TNBC. TTK and Nek2 are among sixteen kinases that
distinguish poor-prognosis basal/TNBC from better prognosis Luminal subtypes and can identify a
population of Luminal breast cancer patients with poor prognosis. The PI recently published that TTK and
Nek2 mRNAs are significantly overexpressed in breast cancers of NHB women. This is the first report that
finds dysregulated mitotic kinases in breast tumors of women from different races and ethnicities. The team
has also demonstrated that TTK and Nek2 can signal early stages of metastasis (the epithelial-to-
mesenchymal transition, or EMT, cell migration, and invasion through different mechanisms). Therefore, the
team has identified TTK and Nek2 as mitotic kinases that can be targeted in NHB and H/L women to suppress
metastatic TNBC. Given the preliminary results that the co-inhibition of mitotic kinases can suppress cell
migration and invasion to a larger extent than their single inhibition, and that these kinases can drive EMT
through distinct EMT transcription factors, the team proposes the hypothesis that the TTK and Nek2 mitotic
kinases cooperate to signal metastasis in TNBC by activating distinct EMT signal transduction pathways. The
overarching goal of this supplement, and what sets it apart from the parent proposal, is to identify at the
global genomic transcriptional level and the protein phosphorylation levels the mechanisms by which TTK
and Nek2 regulate global EMT pathways in TNBC cells from NHB women, and in TNBC PDX models from
C-H/L and NHB women. This will allow the team to identify the detailed mechanisms by which TTK and Nek2
support early metastasis by identifying the EMT master regulators (EMT transcription factors) whose
expression is modulated by the inactivation of TTK and Nek2 (Sub Aim 1.1), and how the phosphorylation
profile of proteins is involved in cell division, apoptosis, and EMT is affected upon co-inactivation of TTK and
Nek2 (Sub Aim 1.2).
