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

Lucy Ireland, Almudena Santos, Fiona Campbell, Carlos Figueiredo, Lesley Ellies, Ulrike Weyer-Czernilofsky, Thomas Bogenrieder, Michael Schmid, View ORCID ProfileAinhoa Mielgo
doi: https://doi.org/10.1101/165068
Lucy Ireland
1Department of Molecular and Clinical Cancer Medicine. University of Liverpool. Liverpool L69 3GE, UK
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Almudena Santos
1Department of Molecular and Clinical Cancer Medicine. University of Liverpool. Liverpool L69 3GE, UK
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Fiona Campbell
1Department of Molecular and Clinical Cancer Medicine. University of Liverpool. Liverpool L69 3GE, UK
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Carlos Figueiredo
1Department of Molecular and Clinical Cancer Medicine. University of Liverpool. Liverpool L69 3GE, UK
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Lesley Ellies
3Department of Pathology. University of California San Diego. La Jolla, CA-92093. U.S.A.
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Ulrike Weyer-Czernilofsky
2Boehringer Ingelheim RCV GmbH & Co KG Pharmacology and Translational Research, Vienna A-1121, Austria
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Thomas Bogenrieder
4Boehringer Ingelheim RCV GmbH & Co KG Medicine and Translational Research, Vienna, Austria
5Department of Urology, University Hospital Grosshadern, Ludwig-Maximilians-University, Marchioninistrasse 15, 81377 Munich, Germany
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Michael Schmid
1Department of Molecular and Clinical Cancer Medicine. University of Liverpool. Liverpool L69 3GE, UK
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Ainhoa Mielgo
1Department of Molecular and Clinical Cancer Medicine. University of Liverpool. Liverpool L69 3GE, UK
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  • ORCID record for Ainhoa Mielgo
  • For correspondence: amielgo@liverpool.ac.uk
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ABSTRACT

Breast cancer remains the leading cause of cancer death in women due 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 tumours. 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 a pre-clinical breast cancer model 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.

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Posted July 23, 2017.
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Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer
Lucy Ireland, Almudena Santos, Fiona Campbell, Carlos Figueiredo, Lesley Ellies, Ulrike Weyer-Czernilofsky, Thomas Bogenrieder, Michael Schmid, Ainhoa Mielgo
bioRxiv 165068; doi: https://doi.org/10.1101/165068
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Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer
Lucy Ireland, Almudena Santos, Fiona Campbell, Carlos Figueiredo, Lesley Ellies, Ulrike Weyer-Czernilofsky, Thomas Bogenrieder, Michael Schmid, Ainhoa Mielgo
bioRxiv 165068; doi: https://doi.org/10.1101/165068

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