title: Filamin A (FLNA) modulates chemosensitivity to docetaxel in triple-negative breast cancer through the MAPK/ERK pathway.
abstract: A previous RNA interference (RNAi) screen identified filamin A (FLNA) as a potential biomarker to predict chemosensitivity in triple-negative breast cancer (TNBC). However, its ability to modulate chemosensitivity and the underlying mechanism has not been investigated. Genetic manipulation of FLNA expression has been performed in an immortalized noncancerous human mammary epithelial cell line and four TNBC cell lines to investigate its effect on chemosensitivity. Western blot analysis was performed to identify the potential signaling pathway involved. Xenograft mouse model was used to examine the in vivo role of FLNA in modulating chemosensitivity. Overexpression of FLNA conferred chemoresistance to docetaxel in noncancerous human mammary epithelial cells. Knockdown of FLNA sensitized four TNBC cell lines, MDA-MB-231, HCC38, Htb126, and HCC1937 to docetaxel which was reversed by reconstituted FLNA expression. Decreased FLNA expression correlated with decreased activation of ERK. Constitutive activation of ERK2 reversed siFLNA-induced chemosensitization. Inhibition of MEK1 recapitulates the effect of FLNA knockdown. MDA-MB-231 xenograft with FLNA knockdown showed enhanced response to docetaxel compared with control xenograft with increased apoptosis. FLNA can function as a modulator of chemosensitivity to docetaxel in TNBC cells through regulation of the MAPK/ERK pathway both in vitro and in vivo. FLNA may serve as a novel therapeutic target for improvement of chemotherapy efficacy in TNBC.
authors.affiliation: Department of Gland Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050017, Hebei, China.
authors.forename: Pengxin
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Department of Gland Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050017, Hebei, China.
authors.forename: Weiyuan
authors.initials: W
authors.lastname: Ma
authors.affiliation: Department of Gland Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050017, Hebei, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Gland Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050017, Hebei, China.
authors.forename: Leilei
authors.initials: L
authors.lastname: Zang
authors.affiliation: Department of Gland Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050017, Hebei, China.
authors.forename: Zhisheng
authors.initials: Z
authors.lastname: Tian
authors.affiliation: Department of Gland Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050017, Hebei, China. kailzhang@sina.com.
authors.forename: Kaili
authors.initials: K
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D064448:Filamins / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism; D051379:Mice; D034622:RNA Interference; D043823:Taxoids / Q000008:administration & dosage*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C578663:FLNA protein, human; D064448:Filamins; D043823:Taxoids; D000077143:Docetaxel
keywords: Chemoresistance; Docetaxel; FLNA; MAPK/ERK; Triple-negative breast cancer