title: Clinical significance of CYLD downregulation in breast cancer.
abstract: Cylindromatosis (CYLD) is a tumor suppressor gene that is mutated in familial cylindromatosis, a rare autosomal dominant disorder associated with numerous benign skin adnexal tumors. CYLD is now known to regulate various signaling pathways, including transforming growth factor-β signaling, Wnt/β-catenin signaling, and NF-κB signaling by deubiquitinating upstream regulatory factors. Downregulation of CYLD has been reported in several malignancies; however, the clinical significance of CYLD expression in many malignancies, including breast cancer, remains to be elucidated. This study investigated the clinical significance of CYLD in breast cancer and its roles in tumor progression. We evaluated CYLD expression in matched normal breast tissue samples and tumor breast tissue samples from 26 patients with breast cancer and in a series of breast cancer cell lines. In addition, by means of immunohistochemistry, we investigated CYLD protein expression and its clinical significance in 244 breast cancer cases. We also analyzed the effects of CYLD repression or overexpression on breast cancer cell viability, cell migration, and NF-κB activity with or without receptor activator of NF-κB ligand (RANKL) stimulation. Breast cancer tissues demonstrated significantly reduced CYLD mRNA expression compared with normal breast tissues. Downregulation of CYLD promoted cell survival and migratory activities through NF-κB activation, whereas CYLD overexpression inhibited those activities in MDA-MB-231 cells. As an important finding, CYLD overexpression also inhibited RANKL-induced NF-κB activation. Our immunohistochemical analysis revealed that reduced CYLD protein expression was significantly correlated with estrogen receptor negativity, high Ki-67 index, high nuclear grade, decreased disease-free survival, and reduced breast cancer-specific survival in primary breast cancer. Moreover, reduced CYLD expression was an independent factor for poor prognosis in breast cancer. CYLD downregulation may promote breast cancer metastasis via NF-κB activation, including RANKL signaling.
authors.affiliation: Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Hayashi
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.forename: Satoru
authors.initials: S
authors.lastname: Shinriki
authors.forename: Takuya
authors.initials: T
authors.lastname: Nakamura
authors.forename: Jianying
authors.initials: J
authors.lastname: Guo
authors.forename: Aiko
authors.initials: A
authors.lastname: Sueta
authors.forename: Mai
authors.initials: M
authors.lastname: Tomiguchi
authors.forename: Saori
authors.initials: S
authors.lastname: Fujiwara
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Yamamoto-Ibusuki
authors.forename: Kei-Ichi
authors.initials: K
authors.lastname: Murakami
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamashita
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Iwase
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ando
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D000074749:Deubiquitinating Enzyme CYLD; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics*; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*; D051176:beta Catenin / Q000235:genetics
chemical_list: D016328:NF-kappa B; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD