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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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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

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Endogenous control of cell cycle progression by autocrine transforming growth factor beta in breast cancer cells

Sudhakar Ammanamanchi1, Manoranjani P M Tillekeratne, Tien C Ko

  • 1Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

Cancer Research
|April 3, 2004
PubMed

Insights

Restoring TGF-beta receptor type II (RII) in ER(+) breast cancer cells re-establishes autocrine transforming growth factor-beta (TGF-beta) signaling. This inhibits cell cycle progression by inducing CDK inhibitors, controlling cancer cell growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Loss of autocrine transforming growth factor-beta (TGF-beta) activity contributes to tumor progression in epithelial cancers.
  • Estrogen receptor-positive (ER(+)) breast cancer cells often lack functional TGF-beta receptor type II (RII), leading to refractoriness to TGF-beta and malignant behavior.

Purpose of the Study:

  • To investigate the role of endogenous autocrine TGF-beta in controlling cell cycle progression in ER(+) breast cancer cells.
  • To determine if restoring TGF-beta receptor type II (RII) expression can re-establish autocrine TGF-beta activity and inhibit cancer cell growth.

Main Methods:

  • Utilized a tetracycline-inducible RII cDNA expression vector to restore RII in ER(+) breast cancer cells.
  • Assessed cell cycle entry via S phase analysis and gene transcription using a TGF-beta responsive promoter (p3TP-Lux).
  • Performed Histone H1 kinase assays and analyzed cyclin-dependent kinase (CDK) inhibitor expression (p21/waf1/cip1, p27/kip).

Main Results:

  • RII replacement reconstituted autocrine TGF-beta activity, evidenced by delayed S phase entry in transfectants.
  • Tetracycline treatment reversed the S phase delay and decreased transcription from the TGF-beta responsive promoter.
  • Reduced CDK2 kinase activity was observed, linked to induced p21/waf1/cip1 and p27/kip expression and their association with CDK2.

Conclusions:

  • Autocrine TGF-beta signaling, when reconstituted via RII expression, effectively controls ER(+) breast cancer cell growth.
  • This growth control is mediated by the induction of CDK inhibitors p21/waf1/cip1 and p27/kip, which suppress CDK2 activity and delay cell cycle progression.

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