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

Publication date: 20 November 2017
Source:Developmental Cell, Volume 43, Issue 4
Author(s): Sameer S. Bajikar, Chun-Chao Wang, Michael A. Borten, Elizabeth J. Pereira, Kristen A. Atkins, Kevin A. Janes
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.

Graphical abstract

Teaser

Tumor suppressors are frequently inactivated by mutation, deletion, or silencing of the encoding gene. Bajikar et al. identify a tumor-suppressive role for growth-differentiation factor 11 (GDF11) in triple-negative breast cancer and find GDF11 function is lost in this context through deficient protein maturation, causing intracellular accumulation of inactive pro-GDF11 precursor.


http://ift.tt/2zTqDBs