Characterization of 17ß-Estradiol Survival Signaling in Medulloblastoma: Relation to Tumor Growth and IGF1 Signaling

Characterization of 17ß-Estradiol Survival Signaling in Medulloblastoma: Relation to Tumor Growth and IGF1 Signaling

Bibliographic Details
Main Author: Cookman, Clifford
Language:English
Published: University of Cincinnati / OhioLINK 2015
Subjects:
Biology
Medulloblastoma
estrogen
estrogen receptor beta
insulin-like growth factor
brain tumor
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447158097
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-ucin14471580972021-08-03T06:33:43Z Characterization of 17ß-Estradiol Survival Signaling in Medulloblastoma: Relation to Tumor Growth and IGF1 Signaling Cookman, Clifford Biology Medulloblastoma estrogen estrogen receptor beta insulin-like growth factor brain tumor Medulloblastoma has been identified as an estrogen-responsive tumor that expresses estrogen receptor ß and whose growth is regulated by 17ß-estradiol both in vitro and in vivo. However, several clear gaps of knowledge exist with regard to the role of 17ß-estradiol in medulloblastoma. These include the precise mechanism responsible for the growth promoting effect of 17ß-estradiol in medulloblastoma as well as the potential for estrogen receptor inhibition in medulloblastoma treatment. To address these gaps of knowledge and gain a better understanding of the role of 17ß-estradiol in medulloblastoma, several model systems were utilized.Extensive pharmacological studies that utilized the human medulloblastoma cell line, D283Med, were performed to characterize the effect of 17ß-estradiol on cell death and the mechanism responsible for any observed effect. Estrogen protected D283Med cells from cell death and this cytoprotection was observed to be due to the activation of estrogen receptor ß and downstream up-regulation of the insulin-like growth factor 1 pathway. To characterize the efficacy of estrogen receptor inhibition and clarify the role of estrogen receptor ß in medulloblastoma, mouse models of medulloblastoma were utilized. It was observed that inhibition of estrogen receptors by fulvestrant or loss of estrogen receptor ß expression decreased tumor growth. This decreased tumor growth is likely due to decreased activation of the insulin-like growth factor pathway and downstream mediators that increase survival. Lastly, to further support the notion that estrogen receptor inhibition may be an effective medulloblastoma treatment, the effect of estrogen on the chemosensitivity of D283Med cells was evaluated. These experiments were conducted with cisplatin, vincristine and lomustine, which are chemotherapeutics that are currently utilized in medulloblastoma treatment. Estrogen decreased the chemosensitivity of D283Med cells while inhibitors of estrogen receptor ß blocked this effect.Taken together, these studies support the notion that medulloblastoma is an estrogen-responsive tumor and suggest that therapies that inhibit estrogen receptor ß may be effective in inhibiting medulloblastoma tumor growth in humans. Furthermore, estrogen receptor ß inhibition may improve the response rate to current treatments due to its sensitizing effect on medulloblastoma with regard to the cytotoxic effects of chemotherapeutic compounds. 2015 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447158097 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447158097 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.
collection NDLTD
language English
sources NDLTD
topic Biology
Medulloblastoma
estrogen
estrogen receptor beta
insulin-like growth factor
brain tumor
spellingShingle Biology
Medulloblastoma
estrogen
estrogen receptor beta
insulin-like growth factor
brain tumor
Cookman, Clifford
Characterization of 17ß-Estradiol Survival Signaling in Medulloblastoma: Relation to Tumor Growth and IGF1 Signaling
author Cookman, Clifford
author_facet Cookman, Clifford
author_sort Cookman, Clifford
title Characterization of 17ß-Estradiol Survival Signaling in Medulloblastoma: Relation to Tumor Growth and IGF1 Signaling
title_short Characterization of 17ß-Estradiol Survival Signaling in Medulloblastoma: Relation to Tumor Growth and IGF1 Signaling
title_full Characterization of 17ß-Estradiol Survival Signaling in Medulloblastoma: Relation to Tumor Growth and IGF1 Signaling
title_fullStr Characterization of 17ß-Estradiol Survival Signaling in Medulloblastoma: Relation to Tumor Growth and IGF1 Signaling
title_full_unstemmed Characterization of 17ß-Estradiol Survival Signaling in Medulloblastoma: Relation to Tumor Growth and IGF1 Signaling
title_sort characterization of 17ß-estradiol survival signaling in medulloblastoma: relation to tumor growth and igf1 signaling
publisher University of Cincinnati / OhioLINK
publishDate 2015
url http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447158097
work_keys_str_mv AT cookmanclifford characterizationof17ßestradiolsurvivalsignalinginmedulloblastomarelationtotumorgrowthandigf1signaling
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