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Novel Actions of Steroid Receptors that Limit Treatment Response in Breast and Lung Cancers

Patki, Mugdha
http://rave.ohiolink.edu/etdc/view?acc_num=mco1382094235

Abstract Details

2013, Doctor of Philosophy (PhD), University of Toledo, College of Medicine.
The primary physiological role of estrogens is the development of secondary sexual characteristics including development and function of the normal breast, reproductive system, bone homeostasis, cognitive functions and cardiovascular system. Estrogen has also been implicated as a major player in the progression of normal breast epithelial tissue to a carcinoma. The role of estrogens in breast cancer has been studied extensively and mainly attributed to the transcriptional activation of growth genes through the estrogen receptor. Along with activation of genes, estrogen is also responsible for repression of many genes. Anti-estrogens antagonize both gene activation and gene repression by estrogen. However, the significance and physiological relevance of gene repression by estrogen is poorly understood. mRNA profiling of MCF-7 breast cancer cells combined with a detailed gene ontology analysis revealed that the genes repressed by estrogen are mostly involved in tumor progression including invasion, drug resistance, angiogenesis and immune evasion. This study looks at the mechanism and impact of estrogen in repressing these tumor progression genes in breast cancer cells; we found that estrogen suppresses the invasiveness of breast cancer cells in a manner that is antagonized by anti-estrogens and is independent of HER2 status. These studies have implications in understanding the incidence of invasive breast cancer following hormone replacement therapy and long term anti-estrogen treatment and may also aid in the development of superior drugs for adjuvant treatment in breast cancer. Variability in response to chemotherapeutic drugs among patients is a longstanding issue in the treatment of several cancers. Likewise, in advanced lung cancer, patient response to the recently introduced drug, pemetrexed is variable. Pemetrexed is an antifolate approved for the first-line treatment of advanced non-squamous non-small cell lung cancer. Dexamethasone was added to the treatment regimen with pemetrexed to alleviate the serious side effect of severe skin rash observed in many patients. Dexamethasone is administered to patients the day before, the day of and the day after pemetrexed chemotherapy. We show that treatment of non-squamous non-small cell lung cancer cell line models with dexamethasone causes a reduction in the S-phase fraction of cells along with a decrease in the expression of thymidylate synthase and dihydrofolate reductase, which are primary and secondary targets of pemetrexed, respectively. As a consequence of these effects of dexamethasone pemetrexed cytotoxicity is attenuated. The response to dexamethasone is variable among different cell line models. Our correlative and functional studies demonstrate that the variability in pemetrexed sensitivity is causally related to variability in the expression of the glucocorticoid receptor isoform alpha, i.e. cells with relatively lower expression of the receptor fail to respond to dexamethasone and hence are sensitive to pemetrexed. These results could help to predict response to pemetrexed therapy leading to the development of individualized treatment strategies.
Manohar Ratnam, Ph.D. (Committee Chair)
Ivana de la Serna, Ph.D. (Committee Member)
Stephan Patrick, Ph.D. (Committee Member)
Edwin Sanchez, Ph.D. (Committee Member)
Robert Trumbly, Ph.D. (Committee Member)
168 p.
Biomedical Research

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Citations

  • Patki, M. (2013). Novel Actions of Steroid Receptors that Limit Treatment Response in Breast and Lung Cancers [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1382094235

    APA Style (7th edition)

  • Patki, Mugdha. Novel Actions of Steroid Receptors that Limit Treatment Response in Breast and Lung Cancers. 2013. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1382094235.

    MLA Style (8th edition)

  • Patki, Mugdha. "Novel Actions of Steroid Receptors that Limit Treatment Response in Breast and Lung Cancers." Doctoral dissertation, University of Toledo, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=mco1382094235

    Chicago Manual of Style (17th edition)

mco1382094235
828
© 2013, some rights reserved.Creative Commons License Novel Actions of Steroid Receptors that Limit Treatment Response in Breast and Lung Cancers by Mugdha Patki is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.