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SOD1 is essential for oncogene-driven mammary tumor formation but dispensable for normal development and proliferation

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Abstract

We previously reported that the dismutase SOD1 is overexpressed in breast cancer. However, whether SOD1 plays an active role in tumor formation in vivo has never been demonstrated. Further, as luminal cells of normal breast epithelial cells are enriched in SOD1, whether SOD1 is essential for normal mammary gland development has never been determined. We initiated this study to investigate the role of SOD1 in mammary gland tumorigenesis as well as in normal mammary gland development. We crossed the inducible erbB2 (MMTV-iErbB2) and Wnt (MMTV-Wnt) transgenic mice to the SOD1 heterozygote or knockout mice. Our results show that SOD1 is essential for oncogene-driven proliferation, but not normal proliferation of the mammary gland associated with pregnancy or other normal proliferative tissues such as skin and intestines. We show that activation of the oncogene ErbB2 is associated with increased ROS and that high ROS sub-population of ErbB2 cancer cells show elevated SOD1. In the same cells, decrease in SOD1 is associated with an elevation in both apoptosis as well as oncogene-induced senescence. Based on these results, we suggest that SOD1 carries a housekeeping function that maintains ROS levels below a threshold that supports oncogene-dependent proliferation, while allowing escape from oncogene-induced senescence, independently of the oncogene driving tumor formation. These results identify SOD1 as an ideal target for cancer therapy as SOD1 inhibitors hold the potential to prevent the growth of cancers cells of diverse genotypes, activate multiple modes of cell death therefore making acquired resistance more difficult, while sparing normal tissues.

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Acknowledgements

We would like to thank all members of the Germain lab and of the Mount Sinai Flow Cytometry Core, Microscopy Core and Biorepository Core Facility. This study was supported by the NIH R01CA172046 to DG and the NIH supplement to MG. The core facilities used in this study are supported by P30 grant CA196521.

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  1. Department of Medicine, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA

    Maria L. Gomez, Nagma Shah, Timothy C. Kenny, Edmund C. Jenkins Jr. & Doris Germain

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  1. Maria L. Gomez
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Correspondence to Doris Germain.

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Gomez, M.L., Shah, N., Kenny, T.C. et al. SOD1 is essential for oncogene-driven mammary tumor formation but dispensable for normal development and proliferation. Oncogene 38, 5751–5765 (2019). https://doi.org/10.1038/s41388-019-0839-x

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