Abstract
Breast cancer remains the leading cause of cancer death in women owing to metastasis and the development of resistance to established therapies. Macrophages are the most abundant immune cells in the breast tumor microenvironment and can both inhibit and support cancer progression. Thus, gaining a better understanding of how macrophages support cancer could lead to the development of more effective therapies. In this study, we find that breast cancer-associated macrophages express high levels of insulin-like growth factors 1 and 2 (IGFs) and are the main source of IGFs within both primary and metastatic tumors. In total, 75% of breast cancer patients show activation of insulin/IGF-1 receptor signaling and this correlates with increased macrophage infiltration and advanced tumor stage. In patients with invasive breast cancer, activation of Insulin/IGF-1 receptors increased to 87%. Blocking IGF in combination with paclitaxel, a chemotherapeutic agent commonly used to treat breast cancer, showed a significant reduction in tumor cell proliferation and lung metastasis in pre-clinical breast cancer models compared to paclitaxel monotherapy. Our findings provide the rationale for further developing the combination of paclitaxel with IGF blockers for the treatment of invasive breast cancer, and Insulin/IGF1R activation and IGF+ stroma cells as potential biomarker candidates for further evaluation.
Highlights
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Breast cancer is the leading cause of cancer death in females worldwide, and is characterized by a high proliferation rate, an increased capacity to metastasize, and its ability to resist standard therapies [1]
Insulin and insulin-like growth factors and 2 (IGFs)-1 receptors are activated on tumor cells in biopsies from breast cancer patients, and this positively correlates with increased tumor-associated macrophages (TAMs) infiltration and advanced tumor stage
To investigate whether IGFsignaling pathways are activated in invasive breast cancer progression and whether their activation correlates with macrophage infiltration, we first evaluated the activation status of insulin and IGF-1 receptors in biopsies from breast cancer patients, and the levels of infiltrated TAMs
Summary
Breast cancer is the leading cause of cancer death in females worldwide, and is characterized by a high proliferation rate, an increased capacity to metastasize, and its ability to resist standard therapies [1]. Current standard treatments for metastatic disease include radiotherapy and chemotherapy [3, 4]. TNBC has a poorer survival rate, its biology is comparatively less well-understood and currently no effective specific targeted therapy is readily available [5]. Patients with metastatic breast cancer often become resistant to current chemotherapy treatments and as a result account for >90% of breast cancer deaths [7], highlighting the need for new therapeutic targets to treat metastatic burden more effectively
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