title: SIRT1 induces tumor invasion by targeting epithelial mesenchymal transition-related pathway and is a prognostic marker in triple negative breast cancer.
abstract: Absence of therapeutic targets poses a critical hurdle in improving prognosis for patients with triple negative breast cancer (TNBC). We evaluated interaction between SIRT1 and epithelial mesenchymal transition (EMT)-associated proteins as well as the role of combined protein expression as a predictor of lymph node metastasis and clinical outcome in TNBC through in vivo and vitro studies. Three hundred nineteen patients diagnosed with TNBC were chosen, immunohistochemical staining for SIRT1 and EMT-related markers' expression was performed on tissue microarrays, and in vitro experiments with each of the three human TNBC cell lines were carried out. The cohort was reclassified according to the use of adjuvant chemotherapy, tumor size, and AJCC stage to analyze the prognostic role of SIRT1 and EMT-related proteins' expression considering different therapeutic modalities and AJCC stages. Combination of four proteins including SIRT1 and three EMT-related proteins was revealed to be a statistically significant independent predictor of lymph node metastasis in the tumor size cohort as well as in the total patient population. Upon Cox regression analysis, increased expression level of the combined proteins correlated with decreased disease-free survival in the total patients as well as those who received adjuvant chemotherapy and those who had early stage breast cancer. In additional in vitro experiments, inhibition of SIRT1 expression with small interfering RNA (siRNA) suppressed tumor invasion in three different TNBC cell lines, and altered expression levels of EMT-related proteins following SIRT1 gene inhibition were identified on western blotting and fluorescence activated cell sorting (FACS) analysis; on the other hand, no change in expression levels of the cell cycle-related factors was observed. Our analysis showed the potential role of SIRT1 in association with EMT-related factors on tumor invasion, metastasis, and disease-free survival in TNBC, SIRT1, and associated EMT-related markers may offer a new prognostic indicator as well as a novel therapeutic candidate.
authors.affiliation: Department of Pathology, Buchen St. Mary's Hospital, Catholic university, Gyeonggi-do, South Korea.
authors.forename: Min-Sun
authors.initials: MS
authors.lastname: Jin
authors.affiliation: Department of Pathology, Jeju National University Hospital, Jeju, South Korea.
authors.forename: Chang Lim
authors.initials: CL
authors.lastname: Hyun
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: In Ae
authors.initials: IA
authors.lastname: Park
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Yul Ri
authors.initials: YR
authors.lastname: Chung
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Seock-Ah
authors.initials: SA
authors.lastname: Im
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Kyung-Hun
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Department of Surgery, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Hyeong-Gon
authors.initials: HG
authors.lastname: Moon
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea. karlnash@naver.com.
authors.forename: Han Suk
authors.initials: HS
authors.lastname: Ryu
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology* / Q000401:mortality / Q000556:secondary / Q000628:therapy; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000201:enzymology* / Q000401:mortality / Q000556:secondary / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D011379:Prognosis; D016016:Proportional Hazards Models; D056564:Sirtuin 1 / Q000502:physiology*; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D014746:Vimentin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014746:Vimentin; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Disease-free survival; Epithelial mesenchymal transition; Invasion; Metastasis; SIRT1; Triple negative breast cancer