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Extinction of Insulin-Like Growth Factor-I Mitogenic Signaling by Antiestrogen-Stimulated Fas-Associated Protein Tyrosine Phosphatase-1 in Human Breast Cancer Cells

INSERM Unit 148 on Hormones and Cancer 34090 Montpellier, France

Steroidal (ICI 182, 780) and nonsteroidal hydroxytamoxifen (OH-Tam) antiestrogens inhibit growth factor-mitogenic activity in MCF 7 estrogen receptor-positive human breast cancer cells. Cell inhibition is correlated with an increase in membrane protein tyrosine phosphatase (PTP) activity, and the addition of orthovanadate prevents OH-Tam inhibition. After RT-PCR cloning of PTPs expressed in MCF 7 cells with primers to their catalytic domains, we have shown, by differential screening, that the expression of two enzymes, leukocyte common antigen-related PTP (LAR) and Fas-associated PTP-1 (FAP-1), was modulated by antiestrogens. By comparative RT-PCR, in situ hybridization, and Northern blot, LAR and FAP-1 mRNAs accumulation was found to be dose- and time-dependently increased by antiestrogens. To further demonstrate that PTPs were key mediators of antiestrogen-inhibitory action on the growth factor pathway, a panel of stable FAP-1 transfectants expressing low to high levels of antisense mRNAs was established. In these clones, the level of antisense RNA expression was correlated with a reduction in basal levels and a complete inhibition of antiestrogen-stimulated values of PTP activity. When FAP-1 expression was abolished, OH-Tam was no longer able to block insulin-like growth factor I mitogenic activity even though it remained strongly antiestrogenic. However, ICI 182,780 was still inhibitory, indicating that its effect was not exclusively mediated by PTP. Our data first demonstrate that a specifically regulated phosphatase (FAP-1) is implicated in the triggering of negative proliferation signals in breast cancer cells.

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