Endogenous Control of Cell Cycle Progression by Autocrine Transforming Growth Factor β in Breast Cancer Cells

Sudhakar Ammanamanchi, Manoranjani P.M. Tillekeratne, Tien C. Ko, Michael G. Brattain

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Tumor progression due to loss of autocrine negative transforming growth factor-β (TGF-β) activity was reported in various cancers of epithelial origin. Estrogen receptor expressing (ER + ) breast cancer cells are refractory to TGF-β effects and exhibit malignant behavior due to loss or inadequate expression of TGF-β receptor type II (RII). The exogenous TGF-β effects on the modulation of cell cycle machinery were analyzed previously. However, very little is known regarding the endogenous control of cell cycle progression by autocrine TGF-β. In this study, we have used a tetracycline regulatable RII cDNA expression vector to demonstrate that RII replacement reconstitutes autocrine negative TGF-β activity in ER + breast cancer cells as evidenced by the delayed entry into S phase by the RII transfectants. Reversal of the delayed entry into S phase by the RII transfectants in the presence of tetracycline in addition to the decreased steady state transcription from a promoter containing the TGF-β responsive element (p3TP-Lux) by TGF-β neutralizing antibody treatment of the RII transfected cells confirmed that autocrine-negative TGF-β activity was induced in the transfectants. Histone H1 kinase assays indicated that the delayed entry of RII transfectants into phase was associated with markedly reduced cyclin-dependent kinase (CDK)2 kinase activity. This reduction in kinase activity was due to the induction of CDK inhibitors p21/waf1/cip1 and p27/kip, and their association with CDK2. Tetracycline treatment of RII transfectants led to the suppression of p21/waf1/cip1 and p27/kip expression, thus, directly demonstrating induction of CDK inhibitors by autocrine TGF-β leading to growth control of ER + breast cancer cells.

Original languageEnglish (US)
Pages (from-to)2509-2515
Number of pages7
JournalCancer Research
Volume64
Issue number7
DOIs
StatePublished - Apr 1 2004

Fingerprint

Transforming Growth Factors
Cell Cycle Checkpoints
Breast Neoplasms
Tetracycline
S Phase
Phosphotransferases
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinase Inhibitor p21
Growth Factor Receptors
Cyclin-Dependent Kinases
Neutralizing Antibodies
Estrogen Receptors
Neoplasms
Cell Cycle
Complementary DNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Endogenous Control of Cell Cycle Progression by Autocrine Transforming Growth Factor β in Breast Cancer Cells. / Ammanamanchi, Sudhakar; Tillekeratne, Manoranjani P.M.; Ko, Tien C.; Brattain, Michael G.

In: Cancer Research, Vol. 64, No. 7, 01.04.2004, p. 2509-2515.

Research output: Contribution to journalArticle

Ammanamanchi, Sudhakar ; Tillekeratne, Manoranjani P.M. ; Ko, Tien C. ; Brattain, Michael G. / Endogenous Control of Cell Cycle Progression by Autocrine Transforming Growth Factor β in Breast Cancer Cells. In: Cancer Research. 2004 ; Vol. 64, No. 7. pp. 2509-2515.
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