Oncotarget

Research Papers:

SIN3A and SIN3B differentially regulate breast cancer metastasis

Monica J. Lewis, Jianzhong Liu, Emily Falk Libby, Minnkyong Lee, Nigel P.S. Crawford & Douglas R. Hurst _

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Oncotarget. 2016; 7:78713-78725. https://doi.org/10.18632/oncotarget.12805

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Abstract

Monica J. Lewis1, Jianzhong Liu1, Emily Falk Libby1, Minnkyong Lee2, Nigel P.S. Crawford2, Douglas R. Hurst1

1Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

2Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

Correspondence to:

Douglas R. Hurst, email: dhurst@uab.edu

Keywords: SIN3A, SIN3B, breast cancer, invasion, metastasis

Received: April 04, 2016     Accepted: October 16, 2016     Published: October 21, 2016

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.


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