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Involvement of Extracellular Signal-regulated Kinase 2 and Stress-activated Protein Kinase/Jun N-Terminal Kinase Activation by Transforming Growth Factor ß in the Negative Growth Control of Breast Cancer Cells¹

Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033

Although transforming growth factor ß (TGF-ß) is known to be a potent growth inhibitor of breast cancer cells (BCCs), the signaling mechanisms mediating TGF-ß responses have not been defined. We have demonstrated previously that TGF-ß 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-ß 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-ß₃ isoform to activate the signaling component ERK2 in TGF-ß-sensitive BCCs but not in TGF-ß-resistant cells. The ERK2 isoform was activated by 6-fold within 10 min of TGF-ß₃ addition to the TGF-ß-sensitive BCC line Hs578T. Moreover, the IC₅₀ for inhibition of DNA synthesis by TGF-ß₃ in this cell line correlated with the EC₅₀ for TGF-ß₃ activation of ERK2. In contrast, TGF-ß₃ had little effect on either DNA synthesis or ERK2 activation in ZR-75 BCCs lacking the type-II TGF-ß receptors (R_II), or in ZR-75 BCCs stably transfected with R_II yet still TGF-ß resistant. In addition, our data demonstrate that TGF-ß₃ 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-ß₃ treatment. In contrast, TGF-ß₃ did not increase SAPK/JNK activity in the TGF-ß-resistant ZR-75 R_II BCCs. Our data provide the first evidence that TGF-ß activation of ERK2 and SAPK/JNK is associated with negative growth control of BCCs. This is also the first demonstration that TGF-ß can activate the SAPK/JNK type of MAPK and that the TGF-ß₃ isoform can regulate MAPK activity.

¹ This work was supported by NIH Grants CA51452, CA54816, and CA68444 to K. M. M. K. M. M. is the recipient of NIH Research Career Development Award KO4 CA59552.

² To whom requests for reprints should be addressed, at Department of Pharmacology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033. Phone: (717) 531-6789; Fax: (717) 531-5013; E-mail: kmm15@psu.edu.

Received 8/19/96. Accepted 12/20/96.

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