Kaiso depletion attenuates the growth and survival of triple negative breast cancer cells

Abstract

Triple negative breast cancers (TNBC) are highly aggressive and lack specific targeted therapies. Recent studies have reported high expression of the transcription factor Kaiso in triple negative tumors, and this correlates with their increased aggressiveness. However, little is known about the clinical relevance of Kaiso in the growth and survival of TNBCs. Herein, we report that Kaiso depletion attenuates TNBC cell proliferation, and delays tumor onset in mice xenografted with the aggressive MDA-231 breast tumor cells. We further demonstrate that Kaiso depletion attenuates the survival of TNBC cells and increases their propensity for apoptotic-mediated cell death. Notably, Kaiso depletion downregulates BRCA1 expression in TNBC cells expressing mutant-p53 and we found that high Kaiso and BRCA1 expression correlates with a poor overall survival in breast cancer patients. Collectively, our findings reveal a role for Kaiso in the proliferation and survival of TNBC cells, and suggest a relevant role for Kaiso in the prognosis and treatment of TNBCs.

Dancing from bottoms up – Roles of the POZ-ZF transcription factor Kaiso in Cancer

“…It is noteworthy that in breast tumor cells expressing wild-type p53, Kaiso functions in a pro-apoptotic capacity [23]. This supports independent studies showing that Kaiso activates the pro-apoptotic gene APAF1 by forming a protein complex with wild-type p53, which in turn binds and activates the APAF1 promoter [24].…”

“…We have observed a similar phenomenon with Kaiso; its interaction with wild-type p53 activates transcription of pro-apoptotic genes, while its interaction with mutant p53 potentially represses transcription of pro-apoptotic genes (Figure 1) [23, 24]. Additionally, a recent study showed that while Kaiso’s transcriptional activities were mostly repressive in HeLa cells, many pathways were also activated in the presence of Kaiso [25].…”

“…Beyond its role in TNBC metastasis, we more recently demonstrated that Kaiso also plays a critical role in TNBC cell proliferation and survival [23]. Kaiso-depleted MDA-231 cells exhibited delayed tumor onset and reduced expression of the cell proliferation markers Ki67 and PUMA in a murine xenograft model [23].…”

“…Kaiso-depleted MDA-231 cells exhibited delayed tumor onset and reduced expression of the cell proliferation markers Ki67 and PUMA in a murine xenograft model [23]. Kaiso depletion also resulted in increased apoptosis of TNBC cells expressing mutant p53 and up-regulation of the pro-apoptotic genes PUMA and Bax [23]. Intriguingly, BRCA1 expression was reduced in Kaiso-depleted Hs587T and MDA-231 cells, and high co-expression of Kaiso and BRCA1 correlated with poor overall survival of TNBC patients.…”

“…Notably, some TNBC subtypes demonstrate decreased sensitivity to chemotherapeutic agents [85]. Thus our finding that Kaiso-depleted Hs578T and MDA-231 cells exhibit increased Cisplatin sensitivity suggest that Kaiso may promote BRCA-1-mediated chemotherapy resistance in TNBC [23]. …”