Genes & Cancer

Granulin, a novel STAT3-interacting protein, enhances STAT3 transcriptional function and correlates with poorer prognosis in breast cancer

Jennifer E. Yeh1, Simion Kreimer2, Sarah R. Walker1,3, Megan M. Emori1, Hannah Krystal1, Andrea Richardson4, Alexander R. Ivanov2, and David A. Frank1,3

1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

2 Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, MA

3 Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA

4 Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA

Correspondence:

David A. Frank, email:

Keywords: STAT3, interacting protein, breast cancer

Received: December 23, 2014 Accepted: April 14, 2015 Published: April 22, 2015

Abstract

Since the neoplastic phenotype of a cell is largely driven by aberrant gene expression patterns, increasing attention has been focused on transcription factors that regulate critical mediators of tumorigenesis such as signal transducer and activator of transcription 3 (STAT3). As proteins that interact with STAT3 may be key in addressing how STAT3 contributes to cancer pathogenesis, we took a proteomics approach to identify novel STAT3-interacting proteins. We performed mass spectrometry-based profiling of STAT3-containing complexes from breast cancer cells that have constitutively active STAT3 and are dependent on STAT3 function for survival. We identified granulin (GRN) as a novel STAT3-interacting protein that was necessary for both constitutive and maximal leukemia inhibitory factor (LIF)-induced STAT3 transcriptional activity. GRN enhanced STAT3 DNA binding and also increased the time-integrated amount of LIF-induced STAT3 activation in breast cancer cells. Furthermore, silencing GRN neutralized STAT3-mediated tumorigenic phenotypes including viability, clonogenesis, and migratory capacity. In primary breast cancer samples, GRN mRNA levels were positively correlated with STAT3 gene expression signatures and with reduced patient survival. These studies identify GRN as a functionally important STAT3-interacting protein that may serve as an important prognostic biomarker and potential therapeutic target in breast cancer.


PII: 58