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Anti-steroidal and anti-growth factor activities of anti-estrogens
G Freiss1, C Prebois, H Rochefort
1INSERM U 148, Unité Hormones et Cancer, Montpellier, France.
Abstract:
Both steroid hormones, such as estrogens and progestins acting via nuclear receptors, and growth factors, such as EGF, IGF-I and IGF-II acting via transmembrane receptors, are able to modulate the growth of human breast cancer cells. In addition to its anti-estrogenic action requiring estrogen receptor (ER) and leading to growth arrest, we have previously shown that the anti-hormone tamoxifen (Tam) is able to block EGF, insulin and IGF-I mitogenic activities in total absence of estrogens (BBRC, 146,1502,1987). This anti-growth factor activity is observed exclusively in ER + cells and is rescued by estradiol addition, thus suggesting that it is mediated by accessible ER sites. In the same culture conditions, progestins and anti-progestins do not display such an inhibition, whereas retinoic acid does, thus indicating that this anti-growth factor effect is not restricted to ER ligands. To progress in the understanding of this inhibition, we first analyzed how Tam could affect EGF and IGF-I binding in responsive cells. We have shown that Tam neither affects EGF and IGF-I binding to their respective receptors by direct competition nor modulates their affinities. However, our recent data suggest that Tam pretreatment (6 days) of MCF7 cells, which similarly prevents EGF and IGF-I mitogenic activities, results in opposite effects on the concentrations of their binding sites. In conclusion, we propose that some steroid antagonists can inhibit not only the action of agonist ligands of the receptors they are binding to, but can also modulate the action of growth factors by decreasing their receptor concentrations or altering their functionalities.
Insights
Tamoxifen, an estrogen receptor (ER) ligand, inhibits growth factors like EGF and IGF-I in ER-positive breast cancer cells. This occurs by reducing growth factor receptor concentrations, not by direct binding competition.
Area of Science:
- Endocrinology
- Molecular Biology
- Cancer Research
Background:
- Steroid hormones (estrogens, progestins) and growth factors (EGF, IGF-I/II) modulate human breast cancer cell growth via nuclear and transmembrane receptors, respectively.
- Tamoxifen (Tam), an anti-estrogen, inhibits estrogen receptor (ER)-mediated growth but also blocks EGF, insulin, and IGF-I mitogenic activities in ER-positive (ER+) cells, even without estrogens.
Purpose of the Study:
- To investigate the mechanism by which tamoxifen inhibits growth factor mitogenic activities in ER+ breast cancer cells.
- To determine if tamoxifen affects the binding affinity or concentration of EGF and IGF-I receptors.
Main Methods:
- Tamoxifen pretreatment of MCF7 cells (ER+ breast cancer cell line).
- Analysis of EGF and IGF-I binding to their respective receptors.
- Assessment of receptor concentrations and affinities.
Main Results:
- Tamoxifen pretreatment inhibits EGF and IGF-I mitogenic activities in MCF7 cells.
- Tamoxifen does not compete with EGF or IGF-I for binding to their receptors, nor does it alter receptor affinities.
- Tamoxifen pretreatment leads to opposite effects on the concentrations of EGF and IGF-I binding sites.
Conclusions:
- Tamoxifen's anti-growth factor activity in ER+ cells is mediated by accessible ER sites.
- Steroid antagonists like tamoxifen can inhibit growth factor action by decreasing receptor concentrations or altering receptor functionality, beyond their direct ligand-receptor interactions.