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. 2020 May 9;12(5):1197. doi: 10.3390/cancers12051197

Figure 1.

Figure 1

Schematic representation of HOTAIR role in breast cancer (BC) drug resistance mechanisms with details of the main molecular pathways involved. In anti-HER2 treatment-resistant BC cells, the overexpression of HOTAIR leads to: (i) deregulation of HER2-related genes by upregulating the signal transduction pathway PI3K-Akt and downregulating the tumor suppressor gene PTEN with the consequent increase in proliferation, cell growth, and survival; (ii) inhibition of apoptosis by the downregulation of cyclin-dependent kinase inhibitor p27; (iii) induction of EMT by TGF-β, Snail and Vimentin upregulation, and decrease in E-cadherin expression. In endocrine therapy resistant BC cells, the overexpression of HOTAIR leads to the repression of ER and the activation of ER-responsive genes, such as GREB1, TFF1, and c-MYC, promoting cell proliferation. In BC radio-resistant cells, the overexpression of HOTAIR leads to: (i) promotion of cell growth and proliferation by upregulation of the PI3K-Akt pathway; (ii) blockage of apoptosis by downregulating the pro-apoptosis gene BAD and miR-218, normally involved in the repair of radiation-induced DNA damage; (iii) induction of metastatic spread by silencing of HOXD10, a metastasis suppressor gene. In chemo-resistant BC cells, the overexpression of HOTAIR leads to: (i) promotion of cell growth, differentiation, and proliferation by upregulating Cyclin D1, the PI3K-Akt pathway, and the wnt/β-catenin pathway; (ii) inhibition of apoptosis by downregulating cyclin-dependent kinase inhibitors p21 and p27, miR-34a and miR-216, both involved in promoting programmed cell death. The red arrows indicate the upregulated genes, the blue arrows the downregulated genes. HER2: human epidermal growth factor receptor 2, PI3K: Phosphoinositide 3-kinases, Akt: protein kinase B, PTEN: Phosphatase and tensin homolog, TGF-beta: Transforming growth factor beta 1, EMT: epithelial–mesenchymal transition, ER: Estrogen Receptor, GREB1: Growth Regulating Estrogen Receptor Binding 1, TFF1: Transcription Termination Factor 1, c-MYC: myelocytomatosis viral oncogene homolog, BAD: BCL2 antagonist of cell death, HOXD10: Homeobox D10.