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Molecular Medicine

, Volume 14, Issue 5–6, pp 264–275 | Cite as

Differential Expression of Receptor Tyrosine Kinases (RTKs) and IGF-I Pathway Activation in Human Uterine Leiomyomas

  • Linda Yu
  • Katrin Saile
  • Carol D. Swartz
  • Hong He
  • Xiaolin Zheng
  • Grace E. Kissling
  • Xudong Di
  • Shantelle Lucas
  • Stanley J. Robboy
  • Darlene Dixon
Research Article

Abstract

Uterine leiomyomas (fibroids) are benign tumors that are prevalent in women of reproductive age. Research suggests that activated receptor tyrosine kinases (RTKs) play an important role in the enhanced proliferation observed in fibroids. In this study, a phospho-RTK array technique was used to detect RTK activity in leiomyomas compared with myometrial tissue. We found that fifteen out of seventeen RTKs evaluated in this study were highly expressed (P < 0.02–0.03) in the leiomyomas, and included the IGF-I/IGF-IR, EGF/EGFR, FGF/FGF-R, HGF/HGF-R, and PDGF/PDGF-R gene families. Due to the higher protein levels of IGF-IR observed in leiomyomas by us in earlier studies, we decided to focus on the activation of the IGF-IR, its downstream effectors, and MAPKp44/42 to confirm our earlier findings; and validate the significance of the increased IGF-IR phosphorylation observed by RTK array analysis in this study. We used immunolocalization, western blot, or immunoprecipitation studies and confirmed that leiomyomas overexpressed IGF-IRβ and phosphorylated IGF-IRβ. Additionally, we showed that the downstream effectors, Shc, Grb2, and MAPKp44/42 (P < 0.02–0.001) were also overexpressed and involved in IGF-IR signaling in these tumors, while IRS-I, PI3K, and AKT were not. In vitro studies showed that IGF-I (100 ng/mL) increased the proliferation of uterine leiomyoma cells (UtLM) (P < 0.0001), and that phosphorylated IGF-IRβ, Shc, and MAPKp44/42 were also overexpressed in IGF-I-treated UtLM cells (P < 0.05), similar to the tissue findings. A neutralizing antibody against the IGF-IRβ blocked these effects. These data indicate that overexpression of RTKs and, in particular, activation of the IGF-IR signaling pathway through Shc/Grb2/MAPK are important in mediating uterine leiomyoma growth. These data may provide new anti-tumor targets for noninvasive treatment of fibroids.

Notes

Acknowledgment

The authors would like to thank Dr. Gregg Richards for his extensive review of the original version of this manuscript. This research was supported, in part, by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences.

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Copyright information

© Feinstein Institute for Medical Research 2008

Authors and Affiliations

  • Linda Yu
    • 1
  • Katrin Saile
    • 1
  • Carol D. Swartz
    • 2
  • Hong He
    • 1
  • Xiaolin Zheng
    • 1
  • Grace E. Kissling
    • 3
  • Xudong Di
    • 1
  • Shantelle Lucas
    • 1
  • Stanley J. Robboy
    • 4
    • 5
  • Darlene Dixon
    • 1
  1. 1.Department of Health and Human Services (DHHS)Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH)Research Triangle ParkUSA
  2. 2.Environmental Carcinogenesis DivisionUS Environmental Protection AgencyResearch Triangle ParkUSA
  3. 3.Department of Health and Human Services (DHHS)Biostatistics Branch, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH)Research Triangle ParkUSA
  4. 4.Department of PathologyDuke University Medical CenterDurhamUSA
  5. 5.Department of Obstetrics and GynecologyDuke University Medical CenterDurhamUSA

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