Comparison of the characteristic of estrogenic action patterns of beta-HCH and heregulin beta1 in MCF-7 human breast cancer cells.
In this study, we compared the estrogenic action pattern of beta-HCH to another ErbB2 activating agent, heregulin beta1 (HRG), along with 17beta-estradiol and epidermal growth factor, to understand the similarities and differences of their action mechanisms. Not surprisingly, most of the initial test results indicated that the two agents, beta-HCH and HRG, are remarkably similar in several estrogenicity tests. However, in-depth biochemical studies revealed that there are some distinct differences between these two compounds in affecting ErbB2 and ErbB3 at early stages of their action. Immunocoprecipitation and Western blot studies indicated that beta-HCH mainly promotes dimerization of ErbB2 and ErbB3 at early time points, whereas HRG causes their dimerization with a rapid and significant rise in their tyrosine phosphorylation levels. These results indicate that, while both beta-HCH and HRG act through ErbB2, their initial actions differ. To understand the long-term consequence of such differential actions of these two agents, we tested the effect of a number of standard pathway specific inhibitors on their actions to induce foci formation after 2 weeks of exposure. The most conspicuous difference between beta-HCH and HRG in MCF-7 foci formation test was their response to 4-hydroxytamoxifen and LY294002, a PI3K inhibitor, i.e., the action of beta-HCH was inhibited by 4-hydroxytamoxifen but stimulated by LY294002, whereas that of heregulin was suppressed by LY294002 but stimulated by 4-hydroxytamoxifen. It appears, therefore, that the action of the latter relies more heavily on the PI3K route as compared to that of the former which has been shown to mainly act through p42/44 MAPK. These differences may account for their differential sensitivities to 4-hydroxytamoxifen.
Hatakeyama
Mariko
M
Department of Environmental Toxicology and the Center for Environmental Health Sciences, University of California, Davis, CA 95616, USA.
Zou
Enmin
E
Matsumura
Fumio
F
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004357:Drug Synergism; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D001556:Hexachlorocyclohexane / Q000494:pharmacology*; D006801:Humans; D020890:Neuregulin-1 / Q000494:pharmacology*; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D011981:Receptors, Prolactin / Q000235:genetics; D014407:Tumor Cells, Cultured
D004958:Estradiol; D004965:Estrogen Antagonists; D001556:Hexachlorocyclohexane; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D011981:Receptors, Prolactin; C087230:heregulin beta1; C023888:beta-hexachlorocyclohexane