Upregulation of PITX2 Promotes Letrozole Resistance Via Transcriptional Activation of IFITM1 Signaling in Breast Cancer Cells
- Author:
Ying Ying XU
1
;
Hai Ru YU
;
Jia Yi SUN
;
Zhao ZHAO
;
Shuang LI
;
Xin Feng ZHANG
;
Zhi Xuan LIAO
;
Ming Ke CUI
;
Juan LI
;
Chan LI
;
Qiang ZHANG
Author Information
- Publication Type:Original Article
- Keywords: Breast neoplasms; PITX2; Interferons; Letrozole resistance; IFITM1
- MeSH: Apoptosis; Breast Neoplasms; Breast; Cell Death; Heterografts; Immunoblotting; Immunohistochemistry; Interferons; Phosphorylation; Polymerase Chain Reaction; Reverse Transcription; RNA, Small Interfering; Transcription Factors; Transcriptional Activation; Up-Regulation
- From:Cancer Research and Treatment 2019;51(2):576-592
- CountryRepublic of Korea
- Language:English
- Abstract: PURPOSE: Although the interferon α (IFNα) signaling and the paired-like homeodomain transcription factor 2 (PITX2) have both been implicated in the progression of breast cancer (BCa), it remains obscure whether these two pathways act in a coordinated manner. We therefore aimed to elucidate the expression and function of PITX2 during the pathogenesis of endocrine resistance in BCa. MATERIALS AND METHODS: PITX2 expression was assessed in BCa tissues using quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunohistochemistry and in experimentally induced letrozole-resistant BCa cells using RT-qPCR and immunoblotting. Effects of PITX2 deregulation on BCa progression was determined by assessing MTT, apoptosis and xenograft model. Finally, using multiple assays, the transcriptional regulation of interferon-inducible transmembrane protein 1 (IFITM1) by PITX2 was studied at both molecular and functional levels. RESULTS: PITX2 expression was induced in letrozole-resistant BCa tissues and cells, and PITX2 induction by IFNα signaling powerfully protected BCa cells against letrozole insult and potentiated letrozole-resistance. Mechanistically, PITX2 enhanced IFNα-induced AKT activation by transactivating the transcription of IFITM1, thus rendering BCa cells unresponsive to letrozoleelicited cell death. Additionally, ablation of IFITM1 expression using siRNA substantially abolished IFNα-elicited AKT phosphorylation, even in the presence of PITX2 overexpression, thus sensitizing BCa cells to letrozole treatment. CONCLUSION: These results demonstrate that constitutive upregulation of PITX2/IFITM1 cascade is an intrinsic adaptive mechanism during the pathogenesis of letrozole-resistance, and modulation of PITX2/IFITM1 level using different genetic and pharmacological means would thus have a novel therapeutic potential against letrozole resistance in BCa.
