Figure 6

The potential regulatory mechanism of the identified gene switches for breast cancer. A) ESR1 activates the transcription of a microRNA, miR-375, probably by binding to the putative promoter of the microRNA. miR-375 targets and inhibits the expression of RASD1 (ras dexamethasome-induced 1) gene, which is an inhibitor of the ESR1 gene expression. With this positive feedback, ESR1 can activate its own expression by reducing the inhibition of RASD1 through activation of miR-375. This model was suggested by [42]. B) ERBB2 activates the expression and phosphorylation of transcription factor c-Jun, which is able to bind to the promoter of ERBB2 to further induce ERBB2 transcription. This potential positive feedback is likely enhanced through c-Jun dependent activation of BEX2 (brain expressed X-linked 2) gene. This model was suggested by [44]. C) A hypothetical regulatory role of TACSTD2 in breast cancer cells. The activation of TACSTD2 increase the cytoplasmic calcium (Ca2+) level, which could in turn activate CREB and the MAPK/ERK pathway through calmodulin-dependent protein kinases (e.g. CaMKII). The activated MAPK pathway can increase the expression of cyclin D1 and cyclin E as well as reduce the level of CDK inhibitor, p27, to thereby promote cell proliferation. The activated CREB could bind to the promoter of TACSTD2, and form a positive feedback to promote and maintain the ON state of TACSTD2. Tamoxifen resistance is associated with the disregulation (high expression level) of c-Fos, AP-1 and pCREB activation [68], which could possibly be mediated by a constitutive ON state of TACSTD2. Trastuzumab resistance is associated with the disregulation of p27 and cyclin D/E (constitutive activation of cyclin D/E and the reason is unclear) [69], which could be modulated by activation of TACSTD2.