TBC1D9: An Important Modulator of Tumorigenesis in Breast Cancer

SIMPLE SUMMARY: Triple negative breast cancer (TNBC) lacks the expression of hormonal receptors estrogen and progesterone along with the over-expression of human epithelial growth factor receptor 2 (HER2). The lack of these receptors makes the treatment targeting these receptors ineffective. TNBC is classified as the most aggressive BC with heterogeneity among patients, resulting in the lack of an effective treatment that could be used in all TNBC patients. This paper describes the result where we identified a low expression of TBC1D9 gene in all TNBC patients (irrespective of their heterogeneity) as compared to non-TNBCs. Down-regulation of the expression of TBC1D9 in luminal BC and TNBC cell lines results in acquisition of more aggressive phenotype. This might link low expression of TBC1D9 in TNBC with its aggressive nature. These data suggest that modulation of TBC1D9 expression or its effector genes in TNBC patients could provide a new therapeutic hope for all TNBCs. ABSTRACT: Triple-negative breast cancer (TNBC) is a major concern among the different subtypes of breast cancer (BC) due to the lack of effective treatment. In a previous study by our group aimed at understanding the difference between TNBC and non-TNBC tumors, we identified the gene TBC1 domain family member 9 (TBC1D9), the expression of which was lower in TNBC as compared to non-TNBC tumors. In the present study, analysis of TBC1D9 expression in TNBC (n = 58) and non-TNBC (n = 25) patient tumor samples validated that TBC1D9 expression can differentiate TNBC (low) from non-TNBC (high) samples and that expression of TBC1D9 was inversely correlated with grade and proliferative index. Moreover, we found that downregulation of the TBC1D9 gene decreases the proliferation marginally in non-TNBC and was associated with increased migratory and tumorigenic potential in both TNBC and luminal BC cell lines. This increase was mediated by the upregulation of ARL8A, ARL8B, PLK1, HIF1α, STAT3, and SPP1 expression in TBC1D9 knockdown cells. Our results suggest that TBC1D9 expression might limit tumor aggressiveness and that it has a differential expression in TNBC vs. non-TNBC tumors.