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

• Published in: Developmental cell Vol. 43; no. 4; pp. 418 - 435.e13
• Main Authors: Bajikar, Sameer S., Wang, Chun-Chao, Borten, Michael A., Pereira, Elizabeth J., Atkins, Kristen A., Janes, Kevin A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.11.2017
• Subjects: scRNA-seq; stochastic profiling; systems biology; transforming growth factor-β; systems biology; stochastic profiling; scRNA-seq; transforming growth factor-β
• ISSN: 1534-5807; 1878-1551; 1878-1551
• DOI: 10.1016/j.devcel.2017.10.027

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. [Display omitted] •GDF11 promotes epithelial alveolus formation in 3D breast epithelial cultures•GDF11 preserves E-cadherin and ID2 and inhibits TNBC invasion•Maturation of bioactive GDF11 is lost in TNBC due to insufficient PCSK5 activity•Restoring PCSK5 suppresses invasion and metastasis 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.