Abstract 5002: KRT13 promotes stemness and drives metastasis in breast cancer through direct interaction with plakoglobin-desmoplakin complexes regulating c-Myc signaling pathway
Authors: Yin Lijuan , Chu Gina Chia-Yi , Li Qinlong , Yin Liyuan , Lewis Michael , Tighiouart Mourad , Chung Leland W. k. , Zhau Haiyen E. 
Published: August 2018

Abstract
Introduction and Objective: Keratins (KRTs) were reported to interact with multiple cellular proteins and initiate signaling cascades that promote cell proliferation, migration and metastasis in cancers. Keratin13 (KRT13), a member of the intermediate filament proteins, plays important role in breast cancer progression and metastasis. The objectives of this study are to determine the role and molecular mechanism of KRT13 in promoting breast cancer growth and metastatic progression.
Methods and Results: We evaluated KRT13 protein expression in 58 primary breast cancer tissues by immunohistochesmistry and found that KRT13 is overexpressed in metastatic breast cancer specimens (12/18) (p&lt;0.05). KRT13 expression in primary breast cancer is associated with decreased patient overall survival based on publicly available Oncomine gene expression datasets. To understand the functional roles of KRT13 in breast cancer progression and metastasis, we performed studies by overexpressing and knocking down KRT13 and investigating alterations of breast cancer cell behaviors in vitro and tumor growth and metastasis in mice. KRT13-overexpressing MCF7 cells promote and KRT13-knocked down HCC1954 and MDA-MB-468 cells inhibit in vitro cell proliferation, invasion and migration and in vivo tumor growth and metastasis to bone and lung. KRT13 overexpression increased the stemness and mammosphere-forming ability of MCF7 cells compared to vehicle control. KRT13 directly interacted with plakoglobin(γ-catenin) to form complexes with desmoplakin as assessed by mass spectrometry and confirmed by Western blot. KRT13 decreased the expression and nuclear translocation of plakoglobin, abrogated plakoglobin-mediated c-Myc gene suppression, promoted cancer stemness and tumor metastasis. Conversely, genetic silencing of KRT13 in HCC1954 and MDA-MB-468 cells increased nuclear translocation of plakoglobin and enhanced c-Myc suppression, and decreased breast cancer cell growth and stemness in vitro and xenograft tumor formation and metastasis in vivo.
Conclusion: KRT13 exerts a novel function in the regulation of breast cancer cell growth, progression and metastasis via alterations of nuclear translocation of plakoglobin that modulates downstream c-Myc-dependent signaling, inducing stem cell-like phenotype and metastasis of breast cancer. Our findings could reveal potential novel targeting of breast cancer progression and metastasis.
Funded by an NCI P01 CA098912 and a Board of Governors Chair of Cancer Research fund from Cedars-Sinai Medical Center to LWK Chung.
Citation Format: Lijuan Yin, Gina Chia-Yi Chu, Qinlong Li, Liyuan Yin, Michael Lewis, Mourad Tighiouart, Leland W. k. Chung, Haiyen E. Zhau. KRT13 promotes stemness and drives metastasis in breast cancer through direct interaction with plakoglobin-desmoplakin complexes regulating c-Myc signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5002.