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Inhibition of the c-fms proto-oncogene autocrine loop and tumor phenotype in glucocorticoid stimulated human breast carcinoma cells

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Abstract

The c-fms proto-oncogene encoded CSF-1 receptor and its ligand represent a feedback loop, which in a paracrine manner, is well known to promote spread of breast cancers. The role of the autocrine feedback loop in promotion of breast tumor behavior, in particular in vitro, is less well understood. The physiologic stimulation of c-fms expression by glucocorticoids (GCs) in vitro and in vivo magnifies the tumor promoting effect seen in these cells from activated c-fms signaling by CSF-1. Targeted molecular therapy against c-fms could therefore abrogate both complementary feedback loops. Using breast cancer cells endogenously co-expressing receptor and ligand, we used complementary approaches to inhibit c-fms expression and function within this autocrine pathway in the context of GC stimulation. Silencing RNA (shRNA), antisense oligonucleotide therapy (AON), and inhibition of c-fms signaling, were all used to quantitate inhibition of GC-stimulated adhesion, motility, and invasion of human breast cancer cells in vitro. shRNA to c-fms downregulated GC-stimulated c-fms mRNA by fourfold over controls, correlating with over twofold reduction in cellular invasiveness. AON therapy was also able to inhibit GC stimulation of c-fms mRNA, and resulted in threefold less invasiveness and 1.5 to 2-fold reductions in adhesion and motility. Finally, the small-molecule c-fms inhibitor Ki20227 was able to decrease in a dose–response manner, breast cancer cell invasion by up to fourfold. Inhibition of this receptor/ligand pair may have clinical utility in inhibition of the autocrine as well as the known paracrine interactions in breast cancer, thus further supporting use of targeted therapies in this disease.

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Abbreviations

Dex:

Dexamethasone

FCS:

Fetal calf serum

ON:

Overnight

AON:

Antisense oligonucleotide

GC:

Glucocorticoid

qRT-PCR:

Quantitative real time reverse transcriptase polymerase chain reaction

siRNA:

Silencing RNA

shRNA:

Small hairpin RNA

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Acknowledgments

This study is supported by DOD Grant DAMD 17-02-1-0633 (to SKC), Arizona Biomedical Research Commission Grant #0802 (to SKC), and Rodel Foundation (to SKC).

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Authors and Affiliations

  1. Departments of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Rochester, NY, 14642, USA

    Eugene P. Toy

  2. Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520-8063, USA

    Masoud Azodi

  3. GYN Oncology at the Cancer Center, Credentialed by MD Anderson Physicians Network, 6701 Airport Blvd. Suite B127, Mobile, AL, 36608, USA

    William J. Roy

  4. Arizona Cancer Center, University of Arizona, Tucson, AZ, 85724-5024, USA

    Tiffany Lamb, Ho-Hyung Woo & Setsuko K. Chambers

  5. Gynecologic Oncology Associates, University of Rochester, 125 Lattimore Rd., Suite 258, Rochester, NY, 14620, USA

    Eugene P. Toy

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  1. Eugene P. Toy
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  2. Tiffany Lamb
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  3. Masoud Azodi
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Correspondence to Eugene P. Toy.

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Toy, E.P., Lamb, T., Azodi, M. et al. Inhibition of the c-fms proto-oncogene autocrine loop and tumor phenotype in glucocorticoid stimulated human breast carcinoma cells. Breast Cancer Res Treat 129, 411–419 (2011). https://doi.org/10.1007/s10549-010-1247-7

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  • DOI: https://doi.org/10.1007/s10549-010-1247-7

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