Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer

Ireland, L, Santos, A, Campbell, F, Figueiredo, C, Hammond, D ORCID: 0000-0002-6326-8739, Ellies, LG, Weyer-Czernilofsky, U, Bogenrieder, T, Schmid, M and Mielgo, A (2018) Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer. Oncogene, 37 (15). pp. 2022-2036. ISSN 0950-9232

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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.

Item Type:	Article
Uncontrolled Keywords:	Cells, Cultured; Animals; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Humans; Mice; Breast Neoplasms; Paclitaxel; Receptor, IGF Type 1; Insulin-Like Growth Factor I; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome; Drug Screening Assays, Antitumor; Drug Synergism; Female; Antibodies, Neutralizing; Antibodies, Monoclonal, Humanized; Animals; Antibodies, Monoclonal, Humanized; Antibodies, Neutralizing; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cells, Cultured; Drug Screening Assays, Antitumor; Drug Synergism; Female; Humans; Insulin-Like Growth Factor I; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Paclitaxel; Receptor, IGF Type 1; Treatment Outcome; 32 Biomedical and Clinical Sciences; 3211 Oncology and Carcinogenesis; 3204 Immunology; Women's Health; Breast Cancer; Cancer; 6.1 Pharmaceuticals; Cancer; Animals; Antibodies, Monoclonal, Humanized; Antibodies, Neutralizing; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cells, Cultured; Drug Screening Assays, Antitumor; Drug Synergism; Female; Humans; Insulin-Like Growth Factor I; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Paclitaxel; Receptor, IGF Type 1; Treatment Outcome; 1103 Clinical Sciences; 1112 Oncology and Carcinogenesis; Oncology & Carcinogenesis; 3101 Biochemistry and cell biology; 3211 Oncology and carcinogenesis
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RM Therapeutics. Pharmacology
Divisions:	Pharmacy and Biomolecular Sciences
Publisher:	Springer
Date of acceptance:	14 December 2017
Date of first compliant Open Access:	7 July 2026
Date Deposited:	07 Jul 2026 12:33
Last Modified:	07 Jul 2026 12:33
DOI or ID number:	10.1038/s41388-017-0115-x
URI:	https://researchonline.ljmu.ac.uk/id/eprint/28974

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