TY - JOUR
T1 - Defects in emerin–nucleoskeleton binding disrupt nuclear structure and promote breast cancer cell motility and metastasis
AU - Liddane, Alexandra G.
AU - McNamara, Chelsea A.
AU - Campbell, Mallory C.
AU - Mercier, Isabelle
AU - Holaska, James M.
N1 - Funding Information:
We thank the Department of Pharmaceutical Sciences at the University of the Sciences and the Department of Biomedical Sciences at Cooper Medical School of Rowan University for providing laboratory space and funding. This work was supported by a predoctoral grant from the New Jersey Commission on Cancer Research (to A.G. Liddane), a grant from the W.W. Smith Charitable Trust (to J.M. Holaska), and a grant from the National Institute of Arthritis, and Musculoskeletal and Skin Diseases (R15AR069935 to J.M. Holaska). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the W.W. Smith Charitable Trust or the New Jersey Commission on Cancer Research. This work was also supported by Rowan University under the Camden Health Research Initiative. We thank Chris Janetopoulos, Darren Boehning, and Goutham Kodakandla for their helpful insights with volumetric analysis. We thank the members of the Holaska laboratory for the many helpful discussions regarding these studies and preparation of the manuscript.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/7
Y1 - 2021/7
N2 - Nuclear envelope proteins play an important role in regulating nuclear size and structure in cancer. Altered expression of nuclear lamins are found in many cancers and its expression is correlated with better clinical outcomes. The nucleus is the largest organelle in the cell with a diameter between 10 and 20 mm. Nuclear size significantly impacts cell migration. Nuclear structural changes are predicted to impact cancer metastasis by regulating cancer cell migration. Here we show emerin regulates nuclear structure in invasive breast cancer cells to impact cancer metastasis. Invasive breast cancer cells had 40% to 50% less emerin than control cells, which resulted in decreased nuclear size. Overexpression of GFP-emerin in invasive breast cancer cells rescued nuclear size and inhibited migration through 3.0 and 8.0 mm pores. Mutational analysis showed emerin binding to nucleoskeletal proteins was important for its regulation of nuclear structure, migration, and invasion. Importantly, emerin expression inhibited lung metastasis by 91% in orthotopic mouse models of breast cancer. Emerin nucleoskeleton-binding mutants failed to inhibit metastasis. These results support a model whereby emerin binding to the nucleoskeleton regulates nuclear structure to impact metastasis. In this model, emerin plays a central role in metastatic transformation, because decreased emerin expression during transformation causes the nuclear structural defects required for increased cell migration, intravasation, and extravasation. Implications: Modulating emerin expression and function represents new targets for therapeutic interventions of metastasis, because increased emerin expression rescued cancer metastasis.
AB - Nuclear envelope proteins play an important role in regulating nuclear size and structure in cancer. Altered expression of nuclear lamins are found in many cancers and its expression is correlated with better clinical outcomes. The nucleus is the largest organelle in the cell with a diameter between 10 and 20 mm. Nuclear size significantly impacts cell migration. Nuclear structural changes are predicted to impact cancer metastasis by regulating cancer cell migration. Here we show emerin regulates nuclear structure in invasive breast cancer cells to impact cancer metastasis. Invasive breast cancer cells had 40% to 50% less emerin than control cells, which resulted in decreased nuclear size. Overexpression of GFP-emerin in invasive breast cancer cells rescued nuclear size and inhibited migration through 3.0 and 8.0 mm pores. Mutational analysis showed emerin binding to nucleoskeletal proteins was important for its regulation of nuclear structure, migration, and invasion. Importantly, emerin expression inhibited lung metastasis by 91% in orthotopic mouse models of breast cancer. Emerin nucleoskeleton-binding mutants failed to inhibit metastasis. These results support a model whereby emerin binding to the nucleoskeleton regulates nuclear structure to impact metastasis. In this model, emerin plays a central role in metastatic transformation, because decreased emerin expression during transformation causes the nuclear structural defects required for increased cell migration, intravasation, and extravasation. Implications: Modulating emerin expression and function represents new targets for therapeutic interventions of metastasis, because increased emerin expression rescued cancer metastasis.
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U2 - 10.1158/1541-7786.MCR-20-0413
DO - 10.1158/1541-7786.MCR-20-0413
M3 - Article
C2 - 33771882
AN - SCOPUS:85109436275
SN - 1541-7786
VL - 19
SP - 1196
EP - 1207
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 7
ER -