Long Non-Coding RNA HOTAIR in Breast Cancer Therapy

Abstract

Breast cancer (BC) is the most common cancer type among women, and morbidity and mortality rates are still very high. Despite new innovative therapeutic approaches for all BC molecular subtypes, the discovery of new molecular biomarkers involved in tumor progression has been fundamental for the implementation of personalized treatment strategies and improvement of patient management. Many experimental studies indicate that long non-coding RNAs (lncRNAs) are strongly involved in BC initiation, metastatic progression, and drug resistance. In particular, aberrant expression of HOX transcript antisense intergenic RNA (HOTAIR) lncRNA plays an important role in BC contributing to its progression and represents a predictor of BC metastasis. For its proven prognostic value, HOTAIR could represent a potential therapeutic target in BC. In the present review, we summarize the role of HOTAIR in cancer progression and drug resistance, in particular in BC, and we illustrate the main approaches for silencing it.

Keywords: breast cancer; breast cancer therapy; drug resistance; lncRNA HOTAIR.

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.

Figure 2

Schematic representation of the main cellular processes inhibited or activated by the silencing of HOTAIR in BC cells. HOTAIR knockdown in BC cells leads to the promotion of: (i) sensitivity to radiotherapy, chemotherapy, hormonal therapies and anti-HER2 therapies; (ii) luminal phenotype acquisition with the upregulation of luminal cytokeratins (KRT8), of cell adhesion molecule E-cadherin, and of transcription factor GATA3, responsible of luminal epithelial differentiation in the adult mammary gland. Furthermore, HOTAIR silencing in BC cells leads to the inhibition of: (i) cell growth and proliferation by downregulating the main signaling pathways involved in these cellular processes, such as PI3K/AKT/mTOR and MAPK/ERK pathway, cyclin D1 and proliferation index Ki67; (ii) invasion and migration by downregulation of metalloproteinases; (iii) EMT by upregulating epithelial markers, such as E-cadherin, downregulating mesenchymal markers, such as Vimentin, and TGF-beta signaling; (iv) self-renewal, reducing colonosphere and mammosphere formation; (v) metastatic progression by upregulating metastasis suppressor genes, such as HOXD10, PCDHB5, and PCDH10. The green arrow indicates the activated processes, the symbol † the inhibited ones. KRT8: Keratin 8, GATA3: GATA Binding Protein 3, mTOR: mammalian target of rapamycin, MAPK: mitogen-activated protein kinase, ERK: Extracellular regulated kinases, PCDHB5: Protocadherin Beta 5, PCDH10: Protocadherin 10.