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Metformin and an insulin/IGF-1 receptor inhibitor are synergistic in blocking growth of triple-negative breast cancer

  • Preclinical study
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Abstract

Purpose

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor survival outcomes. Metformin has been shown to have antitumor effects by lowering serum levels of the mitogen insulin and having pleiotropic effects on cancer cell signaling pathways. BMS-754807 is a potent and reversible inhibitor of both insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR). Both drugs have been reported to have some efficacy in TNBC. However, it is unclear whether the combination of the two drugs is more effective than single drug treatment in TNBC.

Methods

We treated a panel of TNBC cell lines with metformin and BMS-754807 alone and in combination and tested cell viability using MTS assays. We used the CompuSyn software to analyze for additivity, synergism, or antagonism. We also examined the molecular mechanism by performing reverse phase protein assay (RPPA) to detect the candidate pathways altered by single drugs and the drug combination and used Western blotting to verify and expand the findings.

Results

The combination of metformin and BMS-754807 showed synergy in 11 out of 13 TNBC cell lines tested (85%). RPPA analysis detected significant alterations by the drug combination of multiple proteins known to regulate cell cycle and tumor growth. In particular, the drug combination significantly increased levels of total and phosphorylated forms of the cell cycle inhibitor p27Kip1 and decreased the level of the p27Kip1 E3 ligase SCFSkp2.

Conclusions

We conclude that the combination of metformin and BMS-754807 is more effective than either drug alone in inhibiting cell proliferation in the majority of TNBC cell lines, and that one important mechanism may be suppression of SCFSkp2 and subsequent stabilization of the cell cycle inhibitor p27Kip1. This combination treatment may represent an effective targeted therapy for a significant subset of TNBC cases and should be further evaluated.

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Abbreviations

TNBC:

Triple-negative breast cancer

IGF-1R:

Insulin-like growth factor 1 receptor

IGF:

Insulin-like growth factor

IR:

Insulin receptor

ER:

Estrogen receptor

PR:

Progesterone receptor

HER2:

Human epidermal growth factor receptor 2

RPPA:

Reverse phase protein array

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Acknowledgements

This work was supported in part by the following grants: Susan G. Komen Foundation CCR13263802 (S.J.), National Institutes of Health R01CA204926 (Y.L.) and P50CA186784 Project 3 (Y.L.), Cancer Prevention & Research Institute of Texas Proteomics & Metabolomics Core Facility Support Award (Grant No. RP170005) (S.H.), and NCI Cancer Center Support Grant to Antibody-based Proteomics Core/Shared Resource (Grant No. P30CA125123) (S.H.). L.X. was supported in part by a scholarship from the Chinese Scholarship Council (CSC) (Grant Number: 201406860002). We thank Drs. Kimal Rajapakshe and Cristian Coarfa for RPPA data processing and normalization, and Ms. Fuli Jia and Dr. Danli Wu from the Antibody-based Proteomics Core/Shared Resource for their excellent technical assistant in performing RPPA experiments.

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Authors and Affiliations

  1. Laboratory for Comparative Genomics and Bioinformatics, College of Life Science, Nanjing Normal University, 1 Wenyuan Road, Nanjing, 210046, Jiangsu, China

    Lei Xue, Guanyun Wei & Fei Ma

  2. Lester & Sue Smith Breast Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA

    Lei Xue, Fei Yue, Laura Camacho, Sushma Kothapalli, Yi Li & Sao Jiralerspong

  3. Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA

    Shixia Huang

  4. Dan L Duncan Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA

    Fengju Chen, Shixia Huang & Qianxing Mo

  5. Section of Breast Medical Oncology, Division of Hematology and Oncology, University of Arizona Cancer Center, 1515 N. Campbell Ave, Tucson, AZ, 85724, USA

    Sao Jiralerspong

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  1. Lei Xue
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  9. Fei Ma
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  10. Yi Li
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  11. Sao Jiralerspong
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Correspondence to Yi Li or Sao Jiralerspong.

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Xue, L., Chen, F., Yue, F. et al. Metformin and an insulin/IGF-1 receptor inhibitor are synergistic in blocking growth of triple-negative breast cancer. Breast Cancer Res Treat 185, 73–84 (2021). https://doi.org/10.1007/s10549-020-05927-5

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