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Loss of E-cadherin enhances IGF1-IGF1R pathway activation and sensitizes breast cancers to anti-IGF1R inhibitors

Alison M. Nagle, Kevin M. Levine, Nilgun Tasdemir, Julie A. Scott, Kara Burlbaugh, Justin Kehm, Tiffany A. Katz, David N. Boone, Britta M. Jacobsen, Jennifer M. Atkinson, Steffi Oesterreich, Adrian V. Lee
doi: https://doi.org/10.1101/253278
Alison M. Nagle
1Dept. of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA
2Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee Women’s Research Institute, Pittsburgh, PA
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Kevin M. Levine
1Dept. of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA
3Dept. of Pathology, University of Pittsburgh, Pittsburgh, PA
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Nilgun Tasdemir
1Dept. of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA
2Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee Women’s Research Institute, Pittsburgh, PA
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Julie A. Scott
1Dept. of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA
2Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee Women’s Research Institute, Pittsburgh, PA
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Kara Burlbaugh
2Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee Women’s Research Institute, Pittsburgh, PA
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Justin Kehm
2Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee Women’s Research Institute, Pittsburgh, PA
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Tiffany A. Katz
1Dept. of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA
2Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee Women’s Research Institute, Pittsburgh, PA
4The Center for Precision Environmental Health, Dept. of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX (current)
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David N. Boone
2Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee Women’s Research Institute, Pittsburgh, PA
5Dept. of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA
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Britta M. Jacobsen
6Dept. of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO
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Jennifer M. Atkinson
1Dept. of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA
2Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee Women’s Research Institute, Pittsburgh, PA
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Steffi Oesterreich
1Dept. of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA
2Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee Women’s Research Institute, Pittsburgh, PA
3Dept. of Pathology, University of Pittsburgh, Pittsburgh, PA
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Adrian V. Lee
1Dept. of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA
2Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee Women’s Research Institute, Pittsburgh, PA
7Dept. of Human Genetics, University of Pittsburgh, Pittsburgh, PA
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ABSTRACT

Purpose Insulin-like growth factor I (IGF1) signaling regulates breast cancer initiation and progression and associated cancer phenotypes. We previously identified E-cadherin (CDH1) as a repressor of IGF1 signaling and in this study examined how loss of E-cadherin affects IGF1R signaling and response to anti-IGF1R therapies in breast cancer.

Experimental Design Breast cancer cell lines were used to assess how altered E-cadherin levels regulate IGF1R signaling and response to two anti-IGF1R therapies. In situ proximity ligation assay (PLA) was used to define interaction between IGF1R and E-cadherin. TCGA RNA-seq and RPPA data was used to compare IGF1R activation in estrogen receptor positive (ER+) invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) tumors. ER+ ILC cell lines and xenograft tumor explant cultures were used to evaluate efficacy to IGF1R pathway inhibition in combination with endocrine therapy.

Results Diminished functional E-cadherin increased both activation of IGF1R signaling and efficacy to anti-IGF1R therapies. PLA demonstrated a direct endogenous interaction between IGF1R and E-cadherin at points of cell-cell contact. Increased expression of IGF1 ligand and levels of IGF1R phosphorylation were observed in E-cadherin deficient ER+ ILC compared to IDC tumors. IGF1R pathway inhibitors were effective in inhibiting growth in ER+ ILC cell lines and synergized with endocrine therapy and similarly IGF1R inhibition reduced proliferation in ILC tumor explant culture.

Conclusions We provide evidence that loss of E-cadherin hyperactivates the IGF1R pathway and increases sensitivity to IGF1R targeted therapy, thus identifying the IGF1R pathway as a potential novel target in E-cadherin deficient breast cancers.

STATEMENT OF SIGNIFICANCE IGF1R signaling is an attractive therapeutic target in breast cancer due to its regulation of proliferation, migration, and invasion. However, clinical trials targeting IGF1R have largely been unsuccessful due to lack of biomarkers to stratify patients for therapeutic response. In this study, we demonstrate loss of E-cadherin as a potential biomarker for response to anti-IGF1R therapy, and show efficacy of IGF1R inhibition in ER+ ILC in combination with endocrine therapy. Patients with ER+ ILC have poorer long-term outcomes than patients with ER+ IDC and have a propensity for increased late recurrences, highlighting the need for improved therapeutic strategies for this subtype of breast cancer. Here, we credential IGF1R inhibition as a novel therapeutic strategy in combination with endocrine therapy for the treatment of ER+ ILC.

Footnotes

  • Financial support: This study was supported in part by The Breast Cancer Research Foundation (AVL), NIH/NCI R01CA94118 (AVL), NIH T32 GM008424 (AMN), NIH/NCI F30 CA203154 (KML), and Department of Defense Breakthrough Fellowship Award BC160764 (NT).

  • The authors declare no potential conflicts of interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 24, 2018.
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Loss of E-cadherin enhances IGF1-IGF1R pathway activation and sensitizes breast cancers to anti-IGF1R inhibitors
Alison M. Nagle, Kevin M. Levine, Nilgun Tasdemir, Julie A. Scott, Kara Burlbaugh, Justin Kehm, Tiffany A. Katz, David N. Boone, Britta M. Jacobsen, Jennifer M. Atkinson, Steffi Oesterreich, Adrian V. Lee
bioRxiv 253278; doi: https://doi.org/10.1101/253278
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Loss of E-cadherin enhances IGF1-IGF1R pathway activation and sensitizes breast cancers to anti-IGF1R inhibitors
Alison M. Nagle, Kevin M. Levine, Nilgun Tasdemir, Julie A. Scott, Kara Burlbaugh, Justin Kehm, Tiffany A. Katz, David N. Boone, Britta M. Jacobsen, Jennifer M. Atkinson, Steffi Oesterreich, Adrian V. Lee
bioRxiv 253278; doi: https://doi.org/10.1101/253278

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