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dc.contributor.advisorTonetti, Debraen_US
dc.contributor.authorMolloy, Mary E.en_US
dc.date.accessioned2014-06-20T19:12:51Z
dc.date.available2014-06-20T19:12:51Z
dc.date.available2016-06-21T09:30:12Z
dc.date.created2014-05en_US
dc.date.issued2014-06-20
dc.date.submitted2014-05en_US
dc.identifier.urihttp://hdl.handle.net/10027/18899
dc.description.abstractBreast cancer is the most common female malignancy, affecting 1 in 8 women. Resistance to the antiestrogen tamoxifen (TAM), whether de novo or acquired, is a major clinical obstacle. Although recent clinical trials have demonstrated the efficacy of 17β-estradiol (E2) following exhaustive use of antiestrogens, E2 treatment is associated with major side effects such as an increased risk of other gynecological cancers, deterring the clinical community from adopting it as a treatment strategy. Our lab has previously shown that Protein kinase C alpha (PKCα) overexpression predicts TAM resistance in the clinic. Further, the ectopic overexpression of PKCα in T47D breast cancer cells, led to a TAM-resistant, E2-inhibited phenotype in vivo. Here we show that PKCα may be a biomarker for E2-induced growth inhibition. PKCα is overexpressed in a panel of cell lines inhibited by E2 and PKCα knockdown reversed the effects of E2 on cell viability. In addition we sought to identify novel selective estrogen mimics (SEMs), which could achieve the positive therapeutic effects of E2 treatment in TAM-resistant breast cancers, while minimizing the side effects. In vitro screening identified two SEMs, BTC and TTC-352, which displayed estrogenic activity in breast cancer cell lines. BTC and TTC-352 treatment resulted in significant tumor regression in two xenograft models of TAM-resistant, PKCα-overexpressing breast cancer. Interestingly, ERα translocates from the nucleus to the extranuclear sites upon E2 and SEM-induced tumor regression in our T47D:A18/PKCα preclinical TAM-resistant model. SEM treatment, however, did not result in growth of parental, TAM-sensitive xenograft tumors. Endometrial thickening, caused by both E2 and TAM, is directly associated with gynecological carcinogenesis and uterine cancer. Interestingly, SEM treatment did not increase uterine weight in mice suggesting negligible hormonal stimulation in gynecological tissues. Both BTC and TTC-352 resulted in regression of TAM-resistant breast cancer models, while displaying enhanced safety compared to E2 and TAM. These findings suggest the further development of SEMs as a feasible therapeutic strategy for the treatment of TAM-resistant, PKCα overexpressing breast cancer without the side effects associated with E2.en_US
dc.language.isoenen_US
dc.rightsen_US
dc.rightsCopyright 2014 Mary E. Molloyen_US
dc.subjectPKC alpha (Protein kinase C)en_US
dc.subjectbreast canceren_US
dc.subjectendocrine resistanceen_US
dc.titleSelective Estrogen Mimics for the Treatment of Tamoxifen-Resistant, PKCalpha-Overexpressing Breast Canceren_US
thesis.degree.departmentBiopharmaceutical Sciencesen_US
thesis.degree.disciplineBiopharmaceutical Sciencesen_US
thesis.degree.grantorUniversity of Illinois at Chicagoen_US
thesis.degree.levelDoctoralen_US
thesis.degree.namePhD, Doctor of Philosophyen_US
dc.type.genrethesisen_US
dc.contributor.committeeMemberBeck, Williamen_US
dc.contributor.committeeMemberSwanson, Stevenen_US
dc.contributor.committeeMemberOsipo, Clodiaen_US
dc.contributor.committeeMemberThatcher, Gregoryen_US
dc.type.materialtexten_US


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