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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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Tumors initiated by constitutive Cdk2 activation exhibit transforming growth factor beta resistance and acquire

Patrick Corsino1, Bradley Davis, Mary Law

  • 1Department of Pharmacology and Therapeutics and the Shands Cancer Center, University of Florida, Gainesville, Florida, USA.

Cancer Research
|April 6, 2007
PubMed

Insights

Cyclin D1/cyclin-dependent kinase 2 (Cdk2) complexes drive mammary tumors by altering cell cycle regulation and creating a tumor-supportive microenvironment. This mouse model reveals a paracrine loop involving fibroblasts, transforming growth factor beta (TGFβ), and hepatocyte growth factor (HGF).

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Cyclin D1/cyclin-dependent kinase 2 (Cdk2) complexes are frequently observed in human breast cancer.
  • The functional significance of these complexes in breast cancer development remains largely unknown.

Purpose of the Study:

  • To investigate the role of cyclin D1/Cdk2 complexes in mammary tumorigenesis.
  • To elucidate the molecular mechanisms and tumor microenvironment interactions driving tumor progression.

Main Methods:

  • Generated transgenic mice expressing a cyclin D1-Cdk2 fusion protein under the mouse mammary tumor virus (MMTV) promoter.
  • Isolated and characterized cell lines from MMTV-cyclin D1-Cdk2 (MMTV-D1K2) tumors.
  • Analyzed Rb and p130 hyperphosphorylation, E2F-dependent gene expression, and signaling pathways (HGF, TGFβ, c-Met, Akt, p70s6k).

Main Results:

  • MMTV-D1K2 mice developed mammary gland hyperplasia, fibrosis, and tumors.
  • Tumor cells showed Rb and p130 hyperphosphorylation, leading to E2F target gene upregulation.
  • A paracrine loop was identified where MMTV-D1K2 cancer cells secrete TGFβ and interact with fibroblasts, which in turn secrete factors stimulating cancer cell proliferation and c-Met signaling via HGF.

Conclusions:

  • Deregulation of the Cdk/Rb/E2F axis reprograms mammary epithelial cells, initiating a paracrine loop with tumor-associated fibroblasts.
  • This loop involves TGFβ and HGF, contributing to desmoplasia and tumor progression.
  • The MMTV-D1K2 mouse model is valuable for developing therapeutic strategies targeting the stromal desmoplastic reaction in various human tumors.

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