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Autocrine HBEGF expression promotes breast cancer intravasation, metastasis and macrophage-independent invasion in vivo

Oncogene volume 33, pages 3784–3793 (2014)Cite this article

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Abstract

Increased expression of HBEGF in estrogen receptor-negative breast tumors is correlated with enhanced metastasis to distant organ sites and more rapid disease recurrence upon removal of the primary tumor. Our previous work has demonstrated a paracrine loop between breast cancer cells and macrophages in which the tumor cells are capable of stimulating macrophages through the secretion of colony-stimulating factor-1 while the tumor-associated macrophages (TAMs), in turn, aid in tumor cell invasion by secreting epidermal growth factor. To determine how the autocrine expression of epidermal growth factor receptor (EGFR) ligands by carcinoma cells would affect this paracrine loop mechanism, and in particular whether tumor cell invasion depends on spatial ligand gradients generated by TAMs, we generated cell lines with increased HBEGF expression. We found that autocrine HBEGF expression enhanced in vivo intravasation and metastasis and resulted in a novel phenomenon in which macrophages were no longer required for in vivo invasion of breast cancer cells. In vitro studies revealed that expression of HBEGF enhanced invadopodium formation, thus providing a mechanism for cell autonomous invasion. The increased invadopodium formation was directly dependent on EGFR signaling, as demonstrated by a rapid decrease in invadopodia upon inhibition of autocrine HBEGF/EGFR signaling as well as inhibition of signaling downstream of EGFR activation. HBEGF expression also resulted in enhanced invadopodium function via upregulation of matrix metalloprotease 2 (MMP2) and MMP9 expression levels. We conclude that high levels of HBEGF expression can short-circuit the tumor cell/macrophage paracrine invasion loop, resulting in enhanced tumor invasion that is independent of macrophage signaling.

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Acknowledgements

We thank the Condeelis, Cox, Hodgson and Segall labs for their comments and suggestions. We thank Carl Manthey and Johnson and Johnson for providing the JnJ compound. JES is the Betty and Sheldon Feinberg Senior Faculty Scholar in Cancer Research. Funding was provided by CA100324 (ERS, ARB, DC, JWP, JC and JES), CA77522 (JES), T32-GM007288 (ZNZ), a postdoctoral fellowship from the Susan G. Komen for the Cure, KG111405 (VPS), an NIH F32 postdoctoral fellowship F32-CA159663-01 (MRJ) and an NIH 1K12GM102779-01 (EAP).

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Authors and Affiliations

  1. Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA

    Z N Zhou, V P Sharma, B T Beaty, M Roh-Johnson, J S Condeelis & J E Segall

  2. Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA

    E A Peterson & P A Kenny

  3. Department of Molecular Cell Biology, Free University Medical Center, Amsterdam, The Netherlands

    N Van Rooijen

  4. Systems Biology Program, Pacific Northwest National Laboratory, Richland, WA, USA

    H S Wiley

  5. Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, USA

    H S Wiley

  6. Gruss Lipper Center for Biophotonics, Albert Einstein College of Medicine, Bronx, NY, USA

    J S Condeelis & J E Segall

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Correspondence to J E Segall.

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JC has received compensation as a member of the scientific advisory board of MetaStat and owns stock in the company. The other authors declare no conflict of interest.

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Zhou, Z., Sharma, V., Beaty, B. et al. Autocrine HBEGF expression promotes breast cancer intravasation, metastasis and macrophage-independent invasion in vivo. Oncogene 33, 3784–3793 (2014). https://doi.org/10.1038/onc.2013.363

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