Triple-negative breast cancers (TNBCs) represent a subset of breast tumors that are highly aggressive and metastatic, and are responsible for a disproportionate number of breast cancer-related deaths. Several studies have postulated a role for the epithelial-to-mesenchymal transition (EMT) program in the increased aggressiveness and metastatic propensity of TNBCs. Although EMT is essential for early vertebrate development and wound healing, it is frequently co-opted by cancer cells during tumorigenesis. One prominent signaling pathway involved in EMT is the transforming growth factor-β (TGFβ) pathway. In this study, we report that the novel POZ-ZF transcription factor Kaiso is highly expressed in TNBCs and correlates with a shorter metastasis-free survival. Notably, Kaiso expression is induced by the TGFβ pathway and silencing Kaiso expression in the highly invasive breast cancer cell lines, MDA-MB-231 (hereafter MDA-231) and Hs578T, attenuated the expression of several EMT-associated proteins (Vimentin, Slug and ZEB1), abrogated TGFβ signaling and TGFβ-dependent EMT. Moreover, Kaiso depletion attenuated the metastasis of TNBC cells (MDA-231 and Hs578T) in a mouse model. Although high Kaiso and high TGFβR1 expression is associated with poor overall survival in breast cancer patients, overexpression of a kinase-active TGFβR1 in the Kaiso-depleted cells was insufficient to restore the metastatic potential of these cells, suggesting that Kaiso is a key downstream component of TGFβ-mediated pro-metastatic responses. Collectively, these findings suggest a critical role for Kaiso in TGFβ signaling and the metastasis of TNBCs.

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.

PurposeTriple-negative breast cancer (TNBC) is most prevalent in young women of African ancestry (WAA) compared to women of other ethnicities. Recent studies found a correlation between high expression of the transcription factor Kaiso, TNBC aggressiveness, and ethnicity. However, little is known about Kaiso expression and localization patterns in TNBC tissues of WAA. Herein, we analyze Kaiso expression patterns in TNBC tissues of African (Nigerian), Caribbean (Barbados), African American (AA), and Caucasian American (CA) women.MethodsFormalin-fixed and paraffin embedded (FFPE) TNBC tissue blocks from Nigeria and Barbados were utilized to construct a Nigerian/Barbadian tissue microarray (NB-TMA). This NB-TMA and a commercially available TMA comprising AA and CA TNBC tissues (AA-CA-YTMA) were subjected to immunohistochemistry to assess Kaiso expression and subcellular localization patterns, and correlate Kaiso expression with TNBC clinical features.ResultsNigerian and Barbadian women in our study were diagnosed with TNBC at a younger age than AA and CA women. Nuclear and cytoplasmic Kaiso expression was observed in all tissues analyzed. Analysis of Kaiso expression in the NB-TMA and AA-CA-YTMA revealed that nuclear Kaiso H scores were significantly higher in Nigerian, Barbadian, and AA women compared with CA women. However, there was no statistically significant difference in nuclear Kaiso expression between Nigerian versus Barbadian women, or Barbadian versus AA women.ConclusionsHigh levels of nuclear Kaiso expression were detected in patients with a higher degree of African heritage compared to their Caucasian counterparts, suggesting a role for Kaiso in TNBC racial disparity.Electronic supplementary materialThe online version of this article (doi:10.1007/s10552-017-0955-2) contains supplementary material, which is available to authorized users.

Chronic intestinal inflammation contributes to pathologies such as inflammatory bowel disease (IBD) and colon cancer. While the precise etiology remains controversial, IBD is believed to manifest as a result of various factors. We previously reported that intestinal-specific overexpression of the transcription factor Kaiso results in an intestinal inflammatory response; however, the cause of this inflammation is unknown. To elucidate the underlying mechanism(s) of the Kaiso-mediated intestinal inflammatory phenotype, we evaluated two independent transgenic mouse lines that express varying levels of Kaiso ( Kaiso Tg ). Histological analyses of Kaiso Tg mice revealed intestinal damage including thickening of the mucosa, intestinal “lesions” and crypt abscesses, which are reminiscent of IBD pathology. Additionally, higher Kaiso levels induced intestinal neutrophilia as early as 12 weeks, which worsened as the mice aged. Notably, the Kaiso-induced intestinal inflammation correlated with a leaky intestinal barrier and mis-regulation of E-cadherin expression and localization. Interestingly, Kaiso overexpression resulted in reduced proliferation but enhanced migration of intestinal epithelial cells prior to the onset of inflammation. Collectively, these data suggest that Kaiso plays a role in regulating intestinal epithelial cell integrity and function, dysregulation of which contributes to a chronic inflammatory phenotype as mice age.

The metastatic activity of breast carcinomas results from complex genetic changes in epithelial tumor cells and accounts for 90% of deaths in affected patients. Although the invasion of the local lymphatic vessels and veins by malignant breast tumor cells and their subsequent metastasis to the lung, has been recognized, the mechanisms behind the metastatic activity of breast tumor cells to other distal organs and the pathogenesis of metastatic cancer are not well understood. In this study, we utilized derivatives of the well-established and highly metastatic triple negative breast cancer (TNBC) cell line MDA-MB-231 (MDA-231) to study breast tumor metastasis in a mouse model. These MDA-231 derivatives had depleted expression of Kaiso, a POZ-ZF transcription factor that is highly expressed in malignant, triple negative breast cancers. We previously reported that Kaiso depletion attenuates the metastasis of xenografted MDA-231 cells. Herein, we describe the pathological features of the metastatic activity of parental (Kaisopositive) versus Kaisodepleted MDA-231 cells. Both Kaisopositive and Kaisodepleted MDA-231 cells metastasized from the original tumor in the mammary fat pad to the lung. However, while Kaisopositive cells formed large masses in the lung parenchyma, invaded large pulmonary blood vessels and formed secondary metastases and large tumors in the distal organs, Kaisodepleted cells metastasized only to the lung where they formed small metastatic lesions. Importantly, intravascular invasion and secondary metastases in distal organs were not observed in mice xenografted with Kaisodepleted cells. It thus appears that the lung may constitute a barrier for less invasive breast tumors such as the Kaisodepleted TNBC cells; this barrier may limit tumor growth and prevents Kaisodepleted TNBC cells from invading the pulmonary blood vessels and forming secondary metastases in distal organs.