title: HMGA1: a master regulator of tumor progression in triple-negative breast cancer cells.
abstract: Emerging evidence suggests that tumor cells metastasize by co-opting stem cell transcriptional networks, although the molecular underpinnings of this process are poorly understood. Here, we show for the first time that the high mobility group A1 (HMGA1) gene drives metastatic progression in triple negative breast cancer cells (MDA-MB-231, Hs578T) by reprogramming cancer cells to a stem-like state. Silencing HMGA1 expression in invasive, aggressive breast cancer cells dramatically halts cell growth and results in striking morphologic changes from mesenchymal-like, spindle-shaped cells to cuboidal, epithelial-like cells. Mesenchymal genes (Vimentin, Snail) are repressed, while E-cadherin is induced in the knock-down cells. Silencing HMGA1 also blocks oncogenic properties, including proliferation, migration, invasion, and orthotopic tumorigenesis. Metastatic progression following mammary implantation is almost completely abrogated in the HMGA1 knock-down cells. Moreover, silencing HMGA1 inhibits the stem cell property of three-dimensional mammosphere formation, including primary, secondary, and tertiary spheres. In addition, knock-down of HMGA1 depletes cancer initiator/cancer stem cells and prevents tumorigenesis at limiting dilutions. We also discovered an HMGA1 signature in triple negative breast cancer cells that is highly enriched in embryonic stem cells. Together, these findings indicate that HMGA1 is a master regulator of tumor progression in breast cancer by reprogramming cancer cells through stem cell transcriptional networks. Future studies are needed to determine how to target HMGA1 in therapy.
authors: Hematology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors: Sandeep N
authors: SN
authors: Shah
authors: Leslie
authors: L
authors: Cope
authors: Weijie
authors: W
authors: Poh
authors: Amy
authors: A
authors: Belton
authors: Sujayita
authors: S
authors: Roy
authors: C Conover
authors: CC
authors: Talbot
authors: Saraswati
authors: S
authors: Sukumar
authors: David L
authors: DL
authors: Huso
authors: Linda M S
authors: LM
authors: Resar
mesh_terms: D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D025741:HMGA1a Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008648:Mesoderm / Q000473:pathology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000473:pathology; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D025741:HMGA1a Protein
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