title: PTTG1 oncogene promotes tumor malignancy via epithelial to mesenchymal transition and expansion of cancer stem cell population.
abstract: The prognosis of breast cancer patients is related to the degree of metastasis. However, the mechanisms by which epithelial tumor cells escape from the primary tumor and colonize at a distant site are not entirely understood. Here, we analyzed expression levels of pituitary tumor-transforming gene-1 (PTTG1), a relatively uncharacterized oncoprotein, in patient-derived breast cancer tissues with corresponding normal breast tissues. We found that PTTG1 is highly expressed in breast cancer patients, compared with normal tissues. Also, PTTG1 expression levels were correlated with the degree of malignancy in breast cancer cell lines; the more migratory and invasive cancer cell lines MDA-MB-231 and BT549 displayed the higher expression levels of PTTG1 than the less migratory and invasive MCF7 and SK-BR3 and normal MCF10A cell lines. By modulating PTTG1 expression levels, we found that PTTG1 enhances the migratory and invasive properties of breast cancer cells by inducing epithelial to mesenchymal transition, as evidenced by altered morphology and epithelial/mesenchymal cell marker expression patterns and up-regulation of the transcription factor Snail. Notably, down-regulation of PTTG1 also suppressed cancer stem cell population in BT549 cells by decreasing self-renewing ability and tumorigenic capacity, accompanying decreasing CD44(high) CD24(low) cells and Sox2 expression. Up-regulation of PTTG1 had the opposite effects, increasing sphere-forming ability and Sox2 expression. Importantly, PTTG1-mediated malignant tumor properties were due, at least in part, to activation of AKT, known to be a key regulator of both EMT and stemness in cancer cells. Collectively, these results suggest that PTTG1 may represent a new therapeutic target for malignant breast cancer.
authors.affiliation: Department of Chemistry, Research Institute for Natural Sciences, Hanyang University College of Medicine, Hanyang University, Seoul 133-791, Korea.
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Yoon
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Kim
authors.forename: Hyejin
authors.initials: H
authors.lastname: Lee
authors.forename: Rae-Kwon
authors.initials: RK
authors.lastname: Kim
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Lim
authors.forename: Ki-Chun
authors.initials: KC
authors.lastname: Yoo
authors.forename: Ga-Haeng
authors.initials: GH
authors.lastname: Lee
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Cui
authors.forename: Yeong Seok
authors.initials: YS
authors.lastname: Oh
authors.forename: Myung Chan
authors.initials: MC
authors.lastname: Gye
authors.forename: Young Yiul
authors.initials: YY
authors.lastname: Lee
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Park
authors.forename: Sungkwan
authors.initials: S
authors.lastname: An
authors.forename: Sang-Gu
authors.initials: SG
authors.lastname: Hwang
authors.forename: Myung-Jin
authors.initials: MJ
authors.lastname: Park
authors.forename: Yongjoon
authors.initials: Y
authors.lastname: Suh
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D064249:Securin; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D009363:Neoplasm Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D064249:Securin; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C578002:pituitary tumor-transforming protein 1, human; D051057:Proto-Oncogene Proteins c-akt