title: SIN3A and SIN3B differentially regulate breast cancer metastasis.
abstract: SIN3 corepressor complexes play important roles in both normal development and breast cancer. Mammalian cells have two paralogs of SIN3 (SIN3A and SIN3B) that are encoded by distinct genes and have unique functions in many developmental processes. However, specific roles for SIN3A and SIN3B in breast cancer progression have not been characterized. We generated stable knockdown cells of SIN3 paralogs individually and in combination using three non-overlapping shRNA. Stable knockdown of SIN3B caused a significant decrease in transwell invasion through Matrigel and decreased the number of invasive colonies when grown in a 3D extracellular matrix. Conversely, stable knockdown of SIN3A significantly increased transwell invasion and increased the number of invasive colonies. These results were corroborated in vivo in which SIN3B knockdown significantly decreased and SIN3A knockdown increased experimental lung metastases. RNA sequencing was used to identify unique targets and biological pathways that were altered upon knockdown of SIN3A compared to SIN3B. Additionally, we analyzed microarray data sets to identify correlations of SIN3A and SIN3B expression with survival in patients with breast cancer. These data sets indicated that high mRNA expression of SIN3A as well as low mRNA expression of SIN3B correlates with longer relapse free survival specifically in patients with triple negative breast cancer which corresponds with our in vitro and in vivo data. These results demonstrate key functional differences between SIN3 paralogs in regulating the process of breast cancer metastasis and suggest metastasis suppressive roles of SIN3A and metastasis promoting roles of SIN3B.
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Monica J
authors: MJ
authors: Lewis
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Jianzhong
authors: J
authors: Liu
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Emily Falk
authors: EF
authors: Libby
authors: Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Minnkyong
authors: M
authors: Lee
authors: Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Nigel P S
authors: NP
authors: Crawford
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Douglas R
authors: DR
authors: Hurst
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D013997:Time Factors; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy
chemical_list: D012333:RNA, Messenger; D012097:Repressor Proteins; C099683:SIN3A transcription factor; C492042:SIN3B protein, human; D056264:Sin3 Histone Deacetylase and Corepressor Complex
keywords: SIN3A; SIN3B; breast cancer; invasion; metastasis