Resistance to transforming growth factor beta and activin due to reduced receptor expression in human breast tumor cell lines.
Loss of sensitivity to growth inhibition by transforming growth factor (TGF)-beta is a phenomenon often observed in human epithelial tumor cells and is linked to malignant progression. We tested a panel of estrogen receptor (ER)-positive and -negative breast cell lines for their sensitivity to TGF-beta and a related member of the TGF-beta superfamily, activin. Both TGF-beta-sensitive (MCF7, Hs578T, and BT20) and -resistant (two T47D variants, ZR75-1, MDA-MB231, and MDA-MB468) cell lines were found, with no strict correlation between ER content and sensitivity to TGF-beta. In contrast, all four ER-positive cell lines were inhibited by activin A, whereas the ER-negative lines were not. To examine whether resistance to TGF-beta and activin resulted from the absence of the corresponding receptors, mRNA expression of the types I and II receptors was studied. TGF-beta receptor II was not expressed in the two T47D variants and was low in ZR75-1 cells. Upon stable transfection of the TGF-beta receptor II in one of the T47D variants, sensitivity to TGF-beta 1 and TGF-beta 2 was restored with respect to inhibition of anchorage-dependent and -independent proliferation, indicating that other signal transduction components are functionally intact. Sensitivity to TGF-beta in the transfectants was dependent on the expression level of the newly introduced receptor. Resistance to activin in the ER-negative cell lines could be explained in BT20 and Hs578T cells, but not in MDA-MB231 and MDA-MB468, by low activin receptor expression. These results show that resistance to TGF-beta and activin is often, but not always, due to reduced expression of the signaling receptor in breast cancer cells. The activin resistance of ER-negative breast tumor cells may be involved in their increased malignancy compared with ER-positive cells.
Kalkhoven
E
E
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht, The Netherlands.
Roelen
B A
BA
de Winter
J P
JP
Mummery
C L
CL
van den Eijnden-van Raaij
A J
AJ
van der Saag
P T
PT
van der Burg
B
B
D028341:Activins; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007265:Inhibins / Q000494:pharmacology*; D008969:Molecular Sequence Data; D011960:Receptors, Estrogen / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D006133:Growth Substances; D011960:Receptors, Estrogen; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D028341:Activins; D007265:Inhibins