Ethnic and racial-specific differences in levels of centrosome-associated mitotic kinases, proliferative and epithelial-to-mesenchymal markers in breast cancers

Abstract

Molecular epidemiology evidence indicates racial and ethnic differences in the aggressiveness and survival of breast cancer. Hispanics/Latinas (H/Ls) and non-Hispanic Black women (NHB) are at higher risk of breast cancer (BC)-related death relative to non-Hispanic white (NHW) women in part because they are diagnosed with hormone receptor-negative (HR) subtype and at higher stages. Since the cell cycle is one of the most commonly deregulated cellular processes in cancer, we propose that the mitotic kinases TTK (or Mps1), TBK1, and Nek2 could be novel targets to prevent breast cancer progression among NHBs and H/Ls. In this study, we calculated levels of TTK, p-TBK1, epithelial (E-cadherin), mesenchymal (Vimentin), and proliferation (Ki67) markers through immunohistochemical (IHC) staining of breast cancer tissue microarrays (TMAs) that includes samples from 6 regions in the Southeast of the United States and Puerto Rico -regions enriched with NHB and H/L breast cancer patients. IHC analysis showed that TTK, Ki67, and Vimentin were significantly expressed in triple-negative (TNBC) tumors relative to other subtypes, while E-cadherin showed decreased expression. TTK correlated with all of the clinical variables but p-TBK1 did not correlate with any of them. TCGA analysis revealed that the mRNA levels of multiple mitotic kinases, including TTK, Nek2, Plk1, Bub1, and Aurora kinases A and B, and transcription factors that are known to control the expression of these kinases (e.g. FoxM1 and E2F1-3) were upregulated in NHBs versus NHWs and correlated with higher aneuploidy indexes in NHB, suggesting that these mitotic kinases may be future novel targets for breast cancer treatment in NHB women.

Altered threonine tyrosine kinase (TTK) expression is associated with adverse clinical outcomes in breast tumors: An in silico approach

“…Finally, our study revealed an intriguing finding, in which threonine tyrosine kinase (TTK) was overexpressed in breast cancer samples from Asian women when compared to Caucasian women, but not in black women. In recent work developed by Rivera's group, a transcriptomic dataset from TCGA (The Cancer Genome Atlas) of 969 women diagnosed with breast cancer was examined for threonine tyrosine kinase (TTK) expression according to self-declared ethnic classification (Rivera-Rivera et al, 2022). It was discovered in this analysis that threonine tyrosine kinase (TTK) was significantly more expressed in black women when compared to white and Hispanic women (Rivera-Rivera et al, 2022).…”

“…In recent work developed by Rivera's group, a transcriptomic dataset from TCGA (The Cancer Genome Atlas) of 969 women diagnosed with breast cancer was examined for threonine tyrosine kinase (TTK) expression according to self-declared ethnic classification (Rivera-Rivera et al, 2022). It was discovered in this analysis that threonine tyrosine kinase (TTK) was significantly more expressed in black women when compared to white and Hispanic women (Rivera-Rivera et al, 2022). At this time, we cannot directly compare our findings with Rivera's study, firstly, Rivera's work did not incorporate sampling of women with Asian race for the analysis of differential expression of threonine tyrosine kinase (TTK) and secondly, our study has the limitation of having a relatively small sample size in the group of Asian and black women, however, together these studies point to the need for investigations of threonine tyrosine kinase (TTK) as a possible population biomarker.…”

Mitotic kinases are emerging therapeutic targets against metastatic breast cancer

“…For example, triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of the estrogen receptor (ER), progesterone receptor (PR) expression, and human epidermal growth factor receptor 2 (HER2) amplification [ 3 , 4 ]. The absence of these receptors renders TNBC insensitive to both hormone therapy and HER2-targeted therapies, making chemotherapy the primary treatment option [ 5 ], therefore limiting the therapeutic options for TNBC [ 6 ]. While TNBC is considered the most aggressive subtype of breast cancer, there are no known effective targeted therapies to date.…”

“…Mitotic kinases such as AURKA and AURKB have gained much attention as potential therapeutic targets against cancer, due to their essential role in the cell cycle, especially during mitosis [ 56 ]. Previous research studies have uncovered that their dysregulation is implicated in several types of cancer, including breast cancer [ 6 , 15 ]. AURKA is one of the mitotic kinases necessary for preparation for cell division.…”

“…These findings suggest that dysregulation in AURKB can suppress crucial cellular processes that ensure the propagation of cancer cells. Previous work in our laboratory has demonstrated that non-Hispanic Black women with TNBC have higher levels of AURKB, and PLK1 relative to non-Hispanic White women [ 6 ]. Another study demonstrated that knocking down the expression of AURKB and PLK1, which is a crucial mitotic kinase for the activation of AURKB, suppresses survivin activity [ 84 ].…”