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Dev Cell. 2017 Nov 20;43(4):418-435.e13. doi: 10.1016/j.devcel.2017.10.027.

Tumor-Suppressor Inactivation of GDF11 Occurs by Precursor Sequestration in Triple-Negative Breast Cancer.

Author information

1
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA.
2
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA; Institute of Molecular Medicine & Department of Medical Science, National Tsing Hua University, Hsinchu 30013, Taiwan.
3
Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
4
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA. Electronic address: kjanes@virginia.edu.

Abstract

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous carcinoma in which various tumor-suppressor genes are lost by mutation, deletion, or silencing. Here we report a tumor-suppressive mode of action for growth-differentiation factor 11 (GDF11) and an unusual mechanism of its inactivation in TNBC. GDF11 promotes an epithelial, anti-invasive phenotype in 3D triple-negative cultures and intraductal xenografts by sustaining expression of E-cadherin and inhibitor of differentiation 2 (ID2). Surprisingly, clinical TNBCs retain the GDF11 locus and expression of the protein itself. GDF11 bioactivity is instead lost because of deficiencies in its convertase, proprotein convertase subtilisin/kexin type 5 (PCSK5), causing inactive GDF11 precursor to accumulate intracellularly. PCSK5 reconstitution mobilizes the latent TNBC reservoir of GDF11 in vitro and suppresses triple-negative mammary cancer metastasis to the lung of syngeneic hosts. Intracellular GDF11 retention adds to the concept of tumor-suppressor inactivation and reveals a cell-biological vulnerability for TNBCs lacking therapeutically actionable mutations.

KEYWORDS:

scRNA-seq; stochastic profiling; systems biology; transforming growth factor-β

PMID:
29161592
PMCID:
PMC5726799
DOI:
10.1016/j.devcel.2017.10.027
[Indexed for MEDLINE]
Free PMC Article

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