It is known that many organochlorine compounds (OC's) act estrogenic as detected by several in vivo and in vitro tests. Yet, some of these may not directly act on the estrogen receptor (ER) as agonists. In the case of human breast cancer, some OC's have been implicated as probably being promoters based on their estrogenic activities. In our preliminary studies we have clearly established in a human breast carcinoma cell line, MCF-7, that o,p'-DDT and beta-HCH at very low doses cause a rise in c-Neu (= c-erbB2) protein tyrosine kinase activity. Such an action is not mediated through ER and appears to be causally related to their actions to eventually cause cellular transformation in this cell line. We have, therefore, hypothesized that c-Neu plays a pivotal role in mediating the estrogenic action of these OC's in the case of MCF-7 cell transformation which is well acknowledged to be a good model for estrogen-dependent carcinogenesis. Our experimental approaches to test this hypothesis are: (1) first to establish toxicological baselines by studying time-, dose-, and structure-dependency of OC induced c-Neu activation, (2) to conduct a parallel long term study on OC's action to induce cellular transformation in terms of increased """"""""foci formation"""""""" to correlate short term action on c-Neu to the long term consequences, (3) to establish the importance of c-Neu in eventual foci formation by synergistic action of c-Neu and E2 as well as growth factors, (4) to clarify the logical steps by which the signal of the initial activation of c-Neu kinase by OC's is related to trigger carcinogenic transformation and (5) to integrate all this information to construct a logical explanation as well as a dosimetric basis of etiology to OC-induced human breast cancer. The PI finally will address the fundamental question of whether c-Neu activation serves as a major gateway in addition to the estrogen receptor for xenobiotics to cause truly estrogenic cellular responses or not.
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