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PREX1 drives spontaneous bone dissemination of ER+ breast cancer cells

Abstract

A significant proportion of breast cancer patients develop bone metastases, but the mechanisms regulating tumor cell dissemination from the primary site to the skeleton remain largely unknown. Using a novel model of spontaneous bone metastasis derived from human ER+ MCF7 cells, molecular profiling revealed increased PREX1 expression in a cell line established from bone-disseminated MCF7 cells (MCF7b), which were more migratory, invasive, and adhesive in vitro compared with parental MCF7 cells, and this phenotype was mediated by PREX1. MCF7b cells grew poorly in the primary tumor site when reinoculated in vivo, suggesting that these cells are primed to grow in the bone, and were enriched in skeletal sites of metastasis over soft tissue sites. Skeletal dissemination from the primary tumor was reversed with PREX1 knockdown, indicating that PREX1 is a key driver of spontaneous dissemination of tumor cells from the primary site to the bone marrow. In breast cancer patients, PREX1 levels are significantly increased in ER+ tumors and associated with invasive disease and distant metastasis. Together, these findings implicate PREX1 in spontaneous bone dissemination and provide a significant advance to the molecular mechanisms by which breast cancer cells disseminate from the primary tumor site to bone.

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Acknowledgements

The authors wish to acknowledge Mr. Joshua Johnson for histological processing and sectioning of tibiae. Flow Cytometry experiments were performed in the VMC Flow Cytometry Shared Resource, which is supported by the Vanderbilt-Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404). The authors wish to acknowledge the expert technical support of the VANGARD core facilities. RPPA data were generated by the RPPA Core facility at MD Anderson Cancer Center (NCI #CA16672). RWJ and MEC are supported in part by and funding for experiments was provided by NIH award R00CA194198 (RWJ). Experiments performed at Vanderbilt were supported in part by scholarship funds from NIH award P30CA068485 Vanderbilt-Ingram Cancer Center Support Grant.

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MEC and RWJ conceptualized the project, performed the experiments, wrote, edited, and reviewed the manuscript.

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Correspondence to Rachelle W. Johnson.

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Clements, M.E., Johnson, R.W. PREX1 drives spontaneous bone dissemination of ER+ breast cancer cells. Oncogene 39, 1318–1334 (2020). https://doi.org/10.1038/s41388-019-1064-3

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