title: Granulin, a novel STAT3-interacting protein, enhances STAT3 transcriptional function and correlates with poorer prognosis in breast cancer.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Yeh
authors.affiliation: Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, MA.
authors.forename: Simion
authors.initials: S
authors.lastname: Kreimer
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA ; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Walker
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Emori
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Krystal
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Richardson
authors.affiliation: Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, MA.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Ivanov
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA ; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: David A
authors.initials: DA
authors.lastname: Frank
keywords: STAT3; breast cancer; interacting protein