TGFβ regulation of mitogen-activated protein kinases in human breast cancer cells

Randall S. Frey, Kathleen M. Mulder

Research output: Contribution to journalArticlepeer-review

61 Scopus citations


We demonstrate herein the ability of transforming growth factor-beta-2 (TGFβ2) to potently activate extracellular signal-regulated kinase 2 (ERK2) in the highly TGFβ-sensitive breast cancer cell (BCC) line Hs578T. The ERK2 isoform was activated by 3-fold within 5 min of TGFβ2 addition to Hs578T cells. However, TGFβ2 only slightly activated ERK2 (1.5-fold) in the partially TGFβ-responsive BCC line MDA-MB-231. The magnitude of the difference in activation of ERK2 by TGFβ2 in the two cell lines paralleled the difference in the IC50 values for TGFβ inhibition of DNA synthesis; the IC50 value in the MDA-MB-231 cells was 32-fold greater than that in the Hs578T cells. Further, our data demonstrate that TGFβ2 activated the stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) type of mitogen-activated protein kinases (MAPKs); maximal induction levels were 2.5-fold above basal values and were attained at 30 min after TGFβ2 treatment. Transient co-transfection of a luciferase reporter construct (3TP-Lux) containing three AP-1 sites and the plasminogen activator inhibitor-1 (PAI-1) promoter, in conjunction with a construct that directs expression of a dominant-negative mutant ERK2 (TAYF) protein, did not block the ability of TGFβ to induce AP-1 or PAI-1 activity. In contrast, TAYF ERK2 was able to block EGF and insulin-induced 3TP-Lux-reporter activity. These results indicate that in these BCCs, the activation of ERK2 by TGFβ is more tightly linked to the ability of TGFβ to inhibit DNA synthesis than to the ability to stimulate promoter regions important for TGFβ production and control of the extracellular matrix. In addition, this is the first demonstration that TGFβ can activate the SAPK/JNK type of MAPK in TGFβ-sensitive human BCCs.

Original languageEnglish (US)
Pages (from-to)41-50
Number of pages10
JournalCancer Letters
Issue number1
StatePublished - Jul 15 1997

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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