Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

PREX1 drives spontaneous bone dissemination of ER+ breast cancer cells

Oncogene volume 39, pages 1318–1334 (2020)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. Early Breast Cancer Trialists’ Collaborative G. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials. Lancet. 2012;379:432–44.

    Google Scholar 

  2. Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006;12(20 Pt 2):6243s–9s.

    PubMed  Google Scholar 

  3. Weilbaecher KN, Guise TA, McCauley LK. Cancer to bone: a fatal attraction. Nat Rev Cancer. 2011;11:411–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Johnson RW, Schipani E, Giaccia AJ. HIF targets in bone remodeling and metastatic disease. Pharm Ther. 2015;150:169–77.

    CAS  Google Scholar 

  5. Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001;27:165–76.

    CAS  PubMed  Google Scholar 

  6. Schröder J, Fietz T, Köhler A, Petersen V, Tesch H, Spring L, et al. Treatment and pattern of bone metastases in 1094 patients with advanced breast cancer—results from the prospective German Tumour Registry Breast Cancer cohort Study. Eur J Cancer. 2017;79:139–48.

    PubMed  Google Scholar 

  7. Han HH, Lee SH, Kim BG, Lee JH, Kang S, Cho NH. Estrogen receptor status predicts late-onset skeletal recurrence in breast cancer patients. Med (Baltim). 2016;95:e2909.

    CAS  Google Scholar 

  8. Savci-Heijink CD, Halfwerk H, Hooijer GK, Horlings HM, Wesseling J, van de Vijver MJ. Retrospective analysis of metastatic behaviour of breast cancer subtypes. Breast Cancer Res Treat. 2015;150:547–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhang XH, Wang Q, Gerald W, Hudis CA, Norton L, Smid M, et al. Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell. 2009;16:67–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Bidwell BN, Slaney CY, Withana NP, Forster S, Cao Y, Loi S, et al. Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. Nat Med. 2012;18:1224–31.

    CAS  PubMed  Google Scholar 

  11. Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordón-Cardo C, et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 2003;3:537–49.

    CAS  PubMed  Google Scholar 

  12. Lawson CD, Ridley AJ. Rho GTPase signaling complexes in cell migration and invasion. J Cell Biol. 2018;217:447–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Porter AP, Papaioannou A, Malliri A. Deregulation of Rho GTPases in cancer. Small GTPases. 2016;7:123–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Kazanietz MG, Caloca MJ. The Rac GTPase in Cancer: from old concepts to new paradigms. Cancer Res. 2017;77:5445–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Montero JC, Seoane S, Ocaña A, Pandiella A. P-Rex1 participates in Neuregulin-ErbB signal transduction and its expression correlates with patient outcome in breast cancer. Oncogene. 2010;30:1059.

    PubMed  Google Scholar 

  16. Sosa MS, Lopez-Haber C, Yang C, Wang H, Lemmon MA, Busillo JM, et al. Identification of the Rac-GEF P-REX1 as an essential mediator of ErbB signaling in breast cancer. Mol Cell. 2010;40:877–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Dillon LM, Bean JR, Yang W, Shee K, Symonds LK, Balko JM, et al. P-REX1 creates a positive feedback loop to activate growth factor receptor, PI3K/AKT, and MEK/ERK signaling in breast cancer. Oncogene. 2015;34:3968–76.

    CAS  PubMed  Google Scholar 

  18. Liu H-J, Ooms LM, Srijakotre N, Man J, Vieusseux J, Waters JE, et al. PtdIns(3,4,5)P(3)-dependent Rac Exchanger 1 (PREX1) Rac-Guanine Nucleotide Exchange Factor (GEF) activity promotes breast cancer cell proliferation and tumor growth via activation of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. J Biol Chem. 2016;291:17258–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Lindsay CR, Lawn S, Campbell AD, Faller WJ, Rambow F, Mort RL, et al. P-Rex1 is required for efficient melanoblast migration and melanoma metastasis. Nat Commun. 2011;2:555.

    PubMed  PubMed Central  Google Scholar 

  20. Qin J, Xie Y, Wang B, Hoshino M, Wolff DW, Zhao J, et al. Upregulation of PIP3-dependent Rac exchanger 1 (P-Rex1) promotes prostate cancer metastasis. Oncogene. 2009;28:1853.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Marotti JD, Muller KE, Tafe LJ, Demidenko E, Miller TW. P-Rex1 expression in invasive breast cancer in relation to receptor status and distant metastatic site. Int J Breast Cancer. 2017;2017:4537532.

    PubMed  PubMed Central  Google Scholar 

  22. Cheng W-Y, Yang T-HO, Anastassiou D. Development of a prognostic model for breast cancer survival in an open challenge environment. Sci Transl Med. 2013;5:181ra50–ra50.

    PubMed  Google Scholar 

  23. Barkan D, Kleinman H, Simmons JL, Asmussen H, Kamaraju AK, Hoenorhoff MJ, et al. Inhibition of metastatic outgrowth from single dormant tumor cells by targeting the cytoskeleton. Cancer Res. 2008;68:6241–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Gustafsson KL, Farman H, Henning P, Lionikaite V, Moverare-Skrtic S, Wu J, et al. The role of membrane ERalpha signaling in bone and other major estrogen responsive tissues. Sci Rep. 2016;6:29473.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. La Rosa P, Pesiri V, Leclercq G, Marino M, Acconcia F. Palmitoylation regulates 17β-estradiol-induced estrogen receptor-α degradation and transcriptional activity. Mol Endocrinol. 2012;26:762–74.

    PubMed  PubMed Central  Google Scholar 

  26. Duplessis TT, Williams CC, Hill SM, Rowan BG. Phosphorylation of Estrogen Receptor α at serine 118 directs recruitment of promoter complexes and gene-specific transcription. Endocrinology. 2011;152:2517–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ali S, Metzger D, Bornert JM, Chambon P. Modulation of transcriptional activation by ligand-dependent phosphorylation of the human oestrogen receptor A/B region. EMBO J. 1993;12:1153–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Sowder ME, Johnson RW. Enrichment and detection of bone disseminated tumor cells in models of low tumor burden. Sci Rep. 2018;8:14299.

    PubMed  PubMed Central  Google Scholar 

  29. Lawson DA, Bhakta NR, Kessenbrock K, Prummel KD, Yu Y, Takai K, et al. Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature. 2015;526:131–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Colak D, Nofal A, Albakheet A, Nirmal M, Jeprel H, Eldali A, et al. Age-specific gene expression signatures for breast tumors and cross-species conserved potential cancer progression markers in young women. PLoS One. 2013;8:e63204–e.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Ma X-J, Dahiya S, Richardson E, Erlander M, Sgroi DC. Gene expression profiling of the tumor microenvironment during breast cancer progression. Breast Cancer Res: Bcr 2009;11:R7–R.

    PubMed  Google Scholar 

  32. Kimbung S, Kovács A, Bendahl P-O, Malmström P, Fernö M, Hatschek T, et al. Claudin-2 is an independent negative prognostic factor in breast cancer and specifically predicts early liver recurrences. Mol Oncol 2014;8:119–28.

    CAS  PubMed  Google Scholar 

  33. Gawrzak S, Rinaldi L, Gregorio S, Arenas EJ, Salvador F, Urosevic J, et al. MSK1 regulates luminal cell differentiation and metastatic dormancy in ER+ breast cancer. Nat Cell Biol. 2018;20:211–21.

    CAS  PubMed  Google Scholar 

  34. Kremer KN, Dinkel BA, Sterner RM, Osborne DG, Jevremovic D, Hedin KE. TCR-CXCR4 signaling stabilizes cytokine mRNA transcripts via a PREX1-Rac1 pathway: implications for CTCL. Blood. 2017;130:982–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Barrio-Real L, Lopez-Haber C, Casado-Medrano V, Goglia AG, Toettcher JE, Caloca MJ, et al. P-Rex1 is dispensable for Erk activation and mitogenesis in breast cancer. Oncotarget. 2018;9:28612–24.

    PubMed  PubMed Central  Google Scholar 

  36. Ryan MB, Finn AJ, Pedone KH, Thomas NE, Der CJ, Cox AD. ERK/MAPK signaling drives overexpression of the Rac-GEF, PREX1, in BRAF- and NRAS-mutant melanoma. Mol Cancer Res: Mcr. 2016;14:1009–18.

    CAS  PubMed  Google Scholar 

  37. Gont A, Daneshmand M, Woulfe J, Lavictoire SJ, Lorimer IAJ. PREX1 integrates G protein-coupled receptor and phosphoinositide 3-kinase signaling to promote glioblastoma invasion. Oncotarget. 2017;8:8559–73.

    PubMed  Google Scholar 

  38. Ganapathy V, Banach-Petrosky W, Xie W, Kareddula A, Nienhuis H, Miles G, et al. Luminal breast cancer metastasis is dependent on estrogen signaling. Clin Exp Metastasis. 2012;29. https://doi.org/10.1007/s10585-012-9466-4.

    CAS  Google Scholar 

  39. Guo X, Wang X-F. Signaling cross-talk between TGF-β/BMP and other pathways. Cell Res. 2009;19:71–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Neuzillet C, Tijeras-Raballand A, Cohen R, Cros J, Faivre S, Raymond E, et al. Targeting the TGFβ pathway for cancer therapy. Pharmacol Ther. 2015;147:22–31.

    CAS  PubMed  Google Scholar 

  41. Rahman MS, Akhtar N, Jamil HM, Banik RS, Asaduzzaman SM. TGF-β/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation. Bone Res. 2015;3:15005.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Johnson RW, Finger EC, Olcina MM, Vilalta M, Aguilera T, Miao Y, et al. Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow. Nat Cell Biol. 2016;18:1078–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Johnson RW, Sun Y, Ho PWM, Chan ASM, Johnson JA, Pavlos NJ, et al. Parathyroid hormone-related protein negatively regulates tumor cell dormancy genes in a PTHR1/Cyclic AMP-independent manner. Front Endocrinol. 2018;9:241.

    Google Scholar 

  44. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio Cancer Genomics Portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.

    Google Scholar 

  45. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1–pl.

    PubMed  PubMed Central  Google Scholar 

  46. Thomas RJ, Guise TA, Yin JJ, Elliott J, Horwood NJ, Martin TJ, et al. Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology. 1999;140:4451–8.

    CAS  PubMed  Google Scholar 

  47. Johnson RW, Nguyen MP, Padalecki SS, Grubbs BG, Merkel AR, Oyajobi BO, et al. TGF-beta promotion of Gli2-induced expression of parathyroid hormone-related protein, an important osteolytic factor in bone metastasis, is independent of canonical Hedgehog signaling. Cancer Res. 2011;71:822–31.

    CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Program in Cancer Biology, Vanderbilt University, Nashville, TN, 37232, USA

    Miranda E. Clements & Rachelle W. Johnson

  2. Vanderbilt Center for Bone Biology, Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Miranda E. Clements & Rachelle W. Johnson

  3. Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Rachelle W. Johnson

Authors
  1. Miranda E. Clements
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rachelle W. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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

Corresponding author

Correspondence to Rachelle W. Johnson.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-019-1064-3

This article is cited by

Search

Advanced search

Quick links