Section 9
Chapter 8,916

Involvement of extracellular signal-regulated kinase 2 and stress-activated protein kinase/Jun N-terminal kinase activation by transforming growth factor beta in the negative growth control of breast cancer cells

Frey, R.S.; Mulder, K.M.

Cancer Research 57(4): 628-633


ISSN/ISBN: 0008-5472
PMID: 9044838
Accession: 008915534

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Although transforming growth factor beta (TGF-beta) is known to be a potent growth inhibitor of breast cancer cells (BCCs), the signaling mechanisms mediating TGF-beta responses have not been defined. We have demonstrated previously that TGF-beta can activate Ras and extracellular signal-regulated kinase (ERK) 1 in untransformed epithelial cells (K. M. Mulder and S. L. Morris, J. Biol. Chem., 267: 5029-5031, 1992; M. T. Hartsough and K. M. Mulder, J. Biol. Chem., 270: 7117-7124,1995). We have also shown that TGF-beta signaling is altered in epithelial cells when Ras activation is blocked (Hartsough et al., J. Biol. Chem., 271: 22368-22375). Here we demonstrate the ability of the TGF-beta-3 isoform to activate the signaling component ERK2 in TGF-beta-sensitive BCCs but not in TGF-beta-resistant cells. The ERK2 isoform was activated by 6-fold within 10 min of TGF-beta-3 addition to the TGF-beta-sensitive BCC line Hs578T. Moreover, the IC-50 for inhibition of DNA synthesis by TGF-beta-3 in this cell line correlated with the EC-50 for TGF-beta-3 activation of ERK2. In contrast, TGF-beta had little effect on either DNA synthesis or ERK2 activation in ZR-75 BCCs lacking the type-11 TGF-beta receptors (R-II), or in ZR-75 BCCs stably transfected with R,, yet still TGF-beta resistant. In addition, our data demonstrate that TGF-beta-3 affected a sustained activation of the stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) type of mitogen-activated protein kinase (MAPK); maximal induction levels were 2.5-fold above basal values and were attained at 30 min after TGF-beta-3 treatment. In contrast, TGF-beta-3 did not increase SAPK/JNK activity in the TGF-beta-resistant ZR-75 R-II, BCCs. Our data provide the first evidence that TGF-beta activation of ERK2 and SAPK/JNK is associated with negative growth control of BCCs. This is also the first demonstration that TGF-beta can activate the SAPK/JNK type of MAPK and that the TGF-beta-3 isoform can regulate MAPK activity.

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