Journal Article

TAK1 mediates microenvironment-triggered autocrine signals and promotes triple-negative breast cancer lung metastasis

Jimenez, Christian, Li, Lin, Elhodaky, Mostafa, Lee, Grace, Iriondo, Oihana, Liu, Yarong, Lang, Julie, Wang, Pin, Yu, Min

2018

Overview

Triple-negative breast cancer (TNBC) is a highly metastatic subtype of breast cancer that has limited therapeutic options. Thus, developing novel treatments for metastatic TNBC is an urgent need. Here, we show that nanoparticle-mediated delivery of transforming growth factor-β1-activated kinase-1 (TAK1) inhibitor 5 Z -7-Oxozeaenol can inhibit TNBC lung metastasis in most animals tested. P38 is a central signal downstream of TAK1 in TNBC cells in TAK1-mediated response to multiple cytokines. Following co-culturing with macrophages or fibroblasts, TNBC cells express interleukin-1 (IL1) or tumor necrosis factor-α (TNFα), respectively. Compared to TAK1 inhibition, suppressing IL1 signaling with recombinant IL1 receptor antagonist (IL1RA) is less efficient in reducing lung metastasis, possibly due to the additional TAK1 signals coming from distinct stromal cells. Together, these observations suggest that TAK1 may play a central role in promoting TNBC cell adaptation to the lung microenvironment by facilitating positive feedback signaling mediated by P38. Approaches targeting the key TAK1-P38 signal could offer a novel means for suppressing TNBC lung metastasis. Therapeutic options for triple-negative breast cancer (TNBC) metastasis are limited. Here they show nanoparticle-mediated delivery of TAK1 inhibitor 5Z-7-Oxozeaenol to inhibit TNBC lung metastasis in mice, and that TAK1 might promote TNBC cell adaptation in lung microenvironment by positive feedback mediated by P38 signaling.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/51 / 14 / 14/5 / 38/77 / 631/67/1347 / 631/67/322 / 631/67/327 / 64 / 64/60 / 82/80 / 96 / Animals / Antineoplastic Agents - administration & dosage / Antineoplastic Agents - chemistry / Autocrine signalling / Breast cancer / Cancer / Cell Line, Tumor / Cytokines / Enzyme inhibitors / Enzyme Inhibitors - administration & dosage / Enzyme Inhibitors - chemistry / Female / Fibroblasts / Humanities and Social Sciences / Humans / Interleukin 1 / Interleukin 1 receptor antagonist / Interleukin-1 - genetics / Interleukin-1 - metabolism / Lactones - administration & dosage / Lactones - chemistry / Lung cancer / Lung Neoplasms - metabolism / Lung Neoplasms - prevention & control / Lung Neoplasms - secondary / Macrophages / MAP Kinase Kinase Kinases - antagonists & inhibitors / MAP Kinase Kinase Kinases - genetics / MAP Kinase Kinase Kinases - metabolism / Metastases / Metastasis / Mice, Inbred BALB C / multidisciplinary / Nanoparticles / Neoplasm Metastasis / p38 Mitogen-Activated Protein Kinases - genetics / p38 Mitogen-Activated Protein Kinases - metabolism / Positive feedback / Resorcinols - administration & dosage / Resorcinols - chemistry / Science / Science (multidisciplinary) / Signal Transduction - drug effects / Stromal cells / TAK1 protein / Test animals / Transforming growth factor / Triple Negative Breast Neoplasms - genetics / Triple Negative Breast Neoplasms - metabolism / Triple Negative Breast Neoplasms - pathology / Triple Negative Breast Neoplasms - physiopathology / Tumor Microenvironment - drug effects / Tumor Necrosis Factor-alpha - genetics / Tumor Necrosis Factor-alpha - metabolism / Tumor necrosis factor-α