Abstract
Triple-negative breast cancer (TNBC) lacks targeted therapies and has a worse prognosis than other breast cancer subtypes, underscoring an urgent need for new therapeutic targets and strategies. IRE1 is an endoplasmic reticulum (ER) stress sensor, whose activation is predominantly linked to the resolution of ER stress and, in the case of severe stress, to cell death. Here we demonstrate that constitutive IRE1 RNase activity contributes to basal production of pro-tumorigenic factors IL-6, IL-8, CXCL1, GM-CSF, and TGFβ2 in TNBC cells. We further show that the chemotherapeutic drug, paclitaxel, enhances IRE1 RNase activity and this contributes to paclitaxel-mediated expansion of tumor-initiating cells. In a xenograft mouse model of TNBC, inhibition of IRE1 RNase activity increases paclitaxel-mediated tumor suppression and delays tumor relapse post therapy. We therefore conclude that inclusion of IRE1 RNase inhibition in therapeutic strategies can enhance the effectiveness of current chemotherapeutics.
Highlights
Triple-negative breast cancer (TNBC) lacks targeted therapies and has a worse prognosis than other breast cancer subtypes, underscoring an urgent need for new therapeutic targets and strategies
Similar to the results obtained in the breast cancer cell lines, the ratio of spliced to total XBP1 was highest in samples derived from basal-like breast cancers compared to luminal samples, and tumorassociated normal tissue (TAN) (Fig. 1c)
The current dogma regarding IRE1 signaling in cancer is very much aligned with its role as a mediator of the unfolded protein response (UPR) facilitating cell survival under stress conditions
Summary
Triple-negative breast cancer (TNBC) lacks targeted therapies and has a worse prognosis than other breast cancer subtypes, underscoring an urgent need for new therapeutic targets and strategies. We demonstrate that constitutive IRE1 RNase activity contributes to basal production of pro-tumorigenic factors IL-6, IL-8, CXCL1, GM-CSF, and TGFβ2 in TNBC cells. The IRE1–XBP1s signaling axis has emerged as a potential therapeutic target in cancer leading to the development of small molecule inhibitors targeting the IRE1 RNase domain[14,15,16,17]. We evaluate the outcome of blocking IRE1 RNase activity in triple-negative breast cancer (TNBC) cells using a small molecule inhibitor—MKC8866. Inhibition of IRE1 RNase activity by MKC8866 in breast cancer cells leads to the decreased production of protumorigenic factors including IL-6, IL-8, chemokine (C-X-C) ligand 1 (CXCL1), transforming growth factor β 2 (TGFβ2), and granulocyte-macrophage-colony-stimulating-factor (GM-CSF), linking constitutive IRE1 RNase activity to maintenance of a protumorigenic secretome. In vivo, MKC8866 administered in combination with paclitaxel enhances the effectiveness of paclitaxel and limits tumor regrowth upon cessation of paclitaxel treatment
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