Development and characterization of variant T47D human breast cancer cells with altered estrogen and antiestrogen responsiveness /
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contalnmant that has gained negative recognition from its vast toxic and biological effects. A positive aspect of TCDD involves its demonstrated antiestrogenic properties observed both in vivo and in idtro. Understanding the m...
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| Format: | Thesis Book |
| Language: | English |
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[Place of publication not identified] :
[publisher not identified] ;
1994.
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| Online Access: | http://proxy.library.tamu.edu/login?url=http://proquest.umi.com/pqdweb?did=741965241&sid=1&Fmt=2&clientId=2945&RQT=309&VName=PQD |
| Summary: | 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contalnmant that has gained negative recognition from its vast toxic and biological effects. A positive aspect of TCDD involves its demonstrated antiestrogenic properties observed both in vivo and in idtro. Understanding the mechanisms underlying these antiestrogenic actions offers potential for the synthesis of less toxic analogues that could provide alternative chemotherapeutic agents for breast cancer treatment. The first phase of this research investigated the effects of TCDD on growth factor- induced proliferation in low passage, wild type T47D human breast cancer cells. The studies demonstrated that TCDD could inhibit TGF-(x- and EGF-induced growth, suggesting that some of its antiestrogenic properties are indirectly mediated via androgenic effects. Breast cancer is a challenging disease to treat in patients and model in idiro due to its highly heterogenous and dynamic nature. Breast cancer ceM elicit differential estrogen- and in tum antiestrogen- responsiveness as a consequence of their evolution from hormonereponsive to honnone-insensitive states. The genetically unstable T47D human breast cancer cell line is commonly used to model breast cancer cells that progress towards hormonal autonomy. The second phase of this research involved growing T47D cells in both estrogen-rich and estrogen-deficient growth conditions in order to derive new breast cancer cell models with altered estrogen and antiestrogen responsiveness. These studies revealed that long-tenn culture in estrogen-deficient growth conditions was conducive for the emergence of T47D cells [designated L(hE-)] with overexpressed estrogen receptor (ER) levels that exhibited low binding to a synthetic estrogen responsive element (ERE) and lack of estrogen stimulation. The third phase of this research involved the further characterization of breast cancer cells grown in estrogen-deficient conditions with a special emphasis on alterations of ERmediated pathways. This aspect was focused because endocrine therapy often fails as a consequence of changes in the ER or ER- mediated responses. Aryl hydrocarbon receptor (AhR)-mediated pathways were also monitored in these cells in order to ascertain if AhRmediated antiestrogens could provide an alternative route of therapy when ER-mediated antiestrogens failed as a consequence of ER alterations. The efficacy of the two receptormediated pathways was evaluated with clinical and prototype antiestrogens. ER levels in the T47D cells significantly increased while their AhR levels decreased when maintained in estrogen-deficient conditions (Med-2). The results of these studies suggest that the hormonal milieu of breast cancer cells plays a significant role in modulating their responsiveness to estrogens and antiestrogens since the unusual ER parameters observed were reversed when the cells were returned to normal media. The studies also suggest that differential ER isoform expression may dictate the observed responses. TCDD demonstrated some antiestrogenic activity in revertant cell populations that exhibited unstable estrogen responsiveness, indicating that an AhR-mediated antiestrogen may confer an efficacious therapeutic alternative for some breast cancer patients. |
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| Item Description: | Vita. "Major Subject: Toxicology". In title, numerals are used. |
| Physical Description: | xiii, 233 leaves : illustrations ; 28 cm. Issued also on microfiche from University Microfilms Inc. |
| Bibliography: | Includes bibliographical references. |