Breast cancer is the most common cancer among women worldwide with hundreds of thousands of new cases diagnosed each year in the United States alone. The discovery of receptors has improved the specificity of diagnoses, enabling development of receptor specific treatments. The discovery of the estrogen receptor (ER), in particular, has led to the development of antiestrogens such as tamoxifen for the treatment of breast cancer. Despite the vast improvement antiestrogens have made, there is still a growing need to find new therapeutic targets to compensate for resistance that is developing to both the antiestrogens and chemotherapy. One potential target discovered in the 1980s is the xc- system, a cystine/glutamate antiporter. As knowledge about this system has increased, it has been found to have many characteristics of a possible target for cancer treatment. This transporter can be aberrantly expressed in many cancers including breast cancer. It is crucial in these cells for the uptake of cystine, which is important for two reasons. First, cystine and the reduced form cysteine are necessary for normal protein formation. Secondly, cysteine inside the cell is the rate limiting precursor for glutathione synthesis and therefore regulates cellular defense against oxidative stress. The drug sulfasalazine (SASP) has been shown to specifically inhibit this system leading to cell stasis and glutathione depletion. Using the ER positive human breast cancer cell line MCF-7, the xc- specific subunit, xCT, mRNA and protein expression were found to decrease following treatment with estradiol. Additionally, estradiol was found to decrease the doubling time of these cells, while sulfasalazine increased the doubling time. Interestingly, it was found that estradiol decreased the doubling time of MCF-7 cells when compared to cells treated with the same concentration of SASP but without estradiol. Similarly, estradiol seems to cause an increase in the concentration of SASP necessary to cause a significant increase in doubling time. We conclude that estradiol does have a regulatory effect on the xc- system. Estradiol also affects a pathway that overwhelms the inhibitory effect of SASP. Finally, we propose that this downregulation of xCT may be due to nongenomic action of the estradiol bound membrane associated ER and activation of protein kinase signaling cascades.
","abstract_html":"<p></p><p>Breast cancer is the most common cancer among women worldwide with hundreds of thousands of new cases diagnosed each year in the United States alone. The discovery of receptors has improved the specificity of diagnoses, enabling development of receptor specific treatments. The discovery of the estrogen receptor (ER), in particular, has led to the development of antiestrogens such as tamoxifen for the treatment of breast cancer. Despite the vast improvement antiestrogens have made, there is still a growing need to find new therapeutic targets to compensate for resistance that is developing to both the antiestrogens and chemotherapy. One potential target discovered in the 1980s is the xc- system, a cystine/glutamate antiporter. As knowledge about this system has increased, it has been found to have many characteristics of a possible target for cancer treatment. This transporter can be aberrantly expressed in many cancers including breast cancer. It is crucial in these cells for the uptake of cystine, which is important for two reasons. First, cystine and the reduced form cysteine are necessary for normal protein formation. Secondly, cysteine inside the cell is the rate limiting precursor for glutathione synthesis and therefore regulates cellular defense against oxidative stress. The drug sulfasalazine (SASP) has been shown to specifically inhibit this system leading to cell stasis and glutathione depletion. Using the ER positive human breast cancer cell line MCF-7, the xc- specific subunit, xCT, mRNA and protein expression were found to decrease following treatment with estradiol. Additionally, estradiol was found to decrease the doubling time of these cells, while sulfasalazine increased the doubling time. Interestingly, it was found that estradiol decreased the doubling time of MCF-7 cells when compared to cells treated with the same concentration of SASP but without estradiol. Similarly, estradiol seems to cause an increase in the concentration of SASP necessary to cause a significant increase in doubling time. We conclude that estradiol does have a regulatory effect on the xc- system. Estradiol also affects a pathway that overwhelms the inhibitory effect of SASP. Finally, we propose that this downregulation of xCT may be due to nongenomic action of the estradiol bound membrane associated ER and activation of protein kinase signaling cascades.</p>","abstract_has_math":false,"creators":["Ellis, Jillian L."],"institution":"University of Cincinnati","degree_name":"MS","degree_level":"masters","degree_discipline":"Pharmacy: Pharmaceutical Sciences","degree_department":null,"school":null,"contributors":["Gregerson, Karen"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2012,"date_issued":"2012","date_published":"2012","updated_at":"2026-07-24T03:36:23Z","subjects":["Pharmaceuticals","xc- transporter","sulfasalazine","breast cancer","cystine","glutamate","glutathione"],"languages":["English"],"rights":["unrestricted","This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://rave.ohiolink.edu/etdc/view?acc_num=ucin1352488961","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Gregerson, Karen"]},{"key":"dc:creator","label":"Author","values":["Ellis, Jillian L."]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2012"]},{"key":"dc:publisher","label":"Institution","values":["University of Cincinnati / OhioLINK"]},{"key":"dc:type","label":"Dc Type","values":["Electronic Thesis or Dissertation"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Pharmacy: Pharmaceutical Sciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["masters"]},{"key":"thesis:degree_name","label":"Degree Name","values":["MS"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Cincinnati"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Pharmaceuticals","xc- transporter","sulfasalazine","breast cancer","cystine","glutamate","glutathione"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["English"]},{"key":"dc:rights","label":"Dc Rights","values":["unrestricted","This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://rave.ohiolink.edu/etdc/view?acc_num=ucin1352488961"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Breast cancer is the most common cancer among women worldwide with hundreds of thousands of new cases diagnosed each year in the United States alone. The discovery of receptors has improved the specificity of diagnoses, enabling development of receptor specific treatments. The discovery of the estrogen receptor (ER), in particular, has led to the development of antiestrogens such as tamoxifen for the treatment of breast cancer. Despite the vast improvement antiestrogens have made, there is still a growing need to find new therapeutic targets to compensate for resistance that is developing to both the antiestrogens and chemotherapy. One potential target discovered in the 1980s is the xc- system, a cystine/glutamate antiporter. As knowledge about this system has increased, it has been found to have many characteristics of a possible target for cancer treatment. This transporter can be aberrantly expressed in many cancers including breast cancer. It is crucial in these cells for the uptake of cystine, which is important for two reasons. First, cystine and the reduced form cysteine are necessary for normal protein formation. Secondly, cysteine inside the cell is the rate limiting precursor for glutathione synthesis and therefore regulates cellular defense against oxidative stress. The drug sulfasalazine (SASP) has been shown to specifically inhibit this system leading to cell stasis and glutathione depletion. Using the ER positive human breast cancer cell line MCF-7, the xc- specific subunit, xCT, mRNA and protein expression were found to decrease following treatment with estradiol. Additionally, estradiol was found to decrease the doubling time of these cells, while sulfasalazine increased the doubling time. Interestingly, it was found that estradiol decreased the doubling time of MCF-7 cells when compared to cells treated with the same concentration of SASP but without estradiol. Similarly, estradiol seems to cause an increase in the concentration of SASP necessary to cause a significant increase in doubling time. We conclude that estradiol does have a regulatory effect on the xc- system. Estradiol also affects a pathway that overwhelms the inhibitory effect of SASP. Finally, we propose that this downregulation of xCT may be due to nongenomic action of the estradiol bound membrane associated ER and activation of protein kinase signaling cascades.
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"],"dc:format":["application/pdf","p.84","484.3 KB"],"dc:identifier":["http://rave.ohiolink.edu/etdc/view?acc_num=ucin1352488961"],"dc:language":["English"],"dc:publisher":["University of Cincinnati / OhioLINK"],"dc:rights":["unrestricted","This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws."],"dc:subject":["Pharmaceuticals","xc- transporter","sulfasalazine","breast cancer","cystine","glutamate","glutathione"],"dc:title":["Effect of Estradiol on xc- in Human Breast Cancer Cells"],"dc:type":["Electronic Thesis or Dissertation"],"thesis:degree_discipline":["Pharmacy: Pharmaceutical Sciences"],"thesis:degree_level":["masters"],"thesis:degree_name":["MS"],"thesis:institution_name":["University of Cincinnati"]},"updated_at":"2026-07-24T03:36:23Z"}