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You searched for +publisher:"Wayne State University" +contributor:("Manohar Ratnam"). Showing records 1 – 2 of 2 total matches.

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Wayne State University

1. Mcfall, Thomas. Mechanisms Of Hormonal Regulation Of Invasiveness And Metastasis Of Luminal Breast Cancer.

Degree: PhD, Cancer Biology, 2017, Wayne State University

ABSTRACT MECHANISMS OF HORMONAL REGULATION OF INVASIVENESS AND METASTASIS OF LUMINAL BREAST CANCER By THOMAS MCFALL December 2017 Advisor: Dr. Manohar Ratnam Major: Cancer Biology Degree: Doctor of Philosophy Over 20% of breast cancer cases present with distal metastasis and they are predominantly of luminal subtypes. As luminal breast cancer is relatively indolent, it is believed that progression to metastasis must occur over many years, generally well into post-menopausal years. Unfortunately, very little is known about the mechanisms by which these hormone receptor positive tumors metastasize, likely in part due to their slow metastatic rates in animal model systems as well. Moreover, the literature lacks adequate mechanistic understanding of cross talk between estradiol (E2) and progesterone, particularly in the context of breast cancer invasion and metastasis. In this thesis, we sought to investigate the roles of estrogen and progesterone and their nuclear receptors to better understand hormonal regulation of metastasis at physiologically relevant hormone levels both pre- and post-menopause. The novelty of our experimental approach and study design is three-fold: 1. exploration of the isoform-specific actions of the progesterone receptor; 2. investigation of selective micro RNA mediated pathways of cross talk between estrogen and progesterone and 3. development of a quantitative lymph node infiltration assay to monitor metastasis of luminal breast cancer in xenograft models. Advisors/Committee Members: Manohar Ratnam.

Subjects/Keywords: Oncology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Mcfall, T. (2017). Mechanisms Of Hormonal Regulation Of Invasiveness And Metastasis Of Luminal Breast Cancer. (Doctoral Dissertation). Wayne State University. Retrieved from https://digitalcommons.wayne.edu/oa_dissertations/1844

Chicago Manual of Style (16th Edition):

Mcfall, Thomas. “Mechanisms Of Hormonal Regulation Of Invasiveness And Metastasis Of Luminal Breast Cancer.” 2017. Doctoral Dissertation, Wayne State University. Accessed July 17, 2019. https://digitalcommons.wayne.edu/oa_dissertations/1844.

MLA Handbook (7th Edition):

Mcfall, Thomas. “Mechanisms Of Hormonal Regulation Of Invasiveness And Metastasis Of Luminal Breast Cancer.” 2017. Web. 17 Jul 2019.

Vancouver:

Mcfall T. Mechanisms Of Hormonal Regulation Of Invasiveness And Metastasis Of Luminal Breast Cancer. [Internet] [Doctoral dissertation]. Wayne State University; 2017. [cited 2019 Jul 17]. Available from: https://digitalcommons.wayne.edu/oa_dissertations/1844.

Council of Science Editors:

Mcfall T. Mechanisms Of Hormonal Regulation Of Invasiveness And Metastasis Of Luminal Breast Cancer. [Doctoral Dissertation]. Wayne State University; 2017. Available from: https://digitalcommons.wayne.edu/oa_dissertations/1844


Wayne State University

2. Rosati, Rayna. New Mechanism Based Approaches For Treating Prostate Cancer.

Degree: PhD, Cancer Biology, 2017, Wayne State University

Prostate cancer (PC) is generally dependent on the androgen signaling axis for tumor growth. PC is managed by androgen deprivation therapy (ADT). The tumors then frequently progress by restoring ADT-resistant AR signaling through mechanisms such as intratumoral androgen synthesis, overexpression of AR, expression of splice variants of AR and alteration in the balance of AR co-regulators. This stage of progression is termed castrate recurrent prostate cancer (CRPC). Moreover, ADT has many major undesirable acute and chronic side effects on various normal tissues. Therefore a more strategic therapy approach is one that would disrupt a functional arm of AR signaling critical for PC/CRPC growth but not for the essential physiological roles of AR in normal adult tissues. This thesis describes two different mechanism-based approaches to develop small molecule drugs that address the above problems. The transcription factor ELK1 tethers the androgen receptor (AR) to chromatin, enabling sustained activation of genes critical for growth in prostate cancer cell lines. The N-terminal A/B domain of AR [AR(A/B)], which excludes the ligand binding pocket of AR, is adequate for interaction with ELK1. This is significant because the major splice variants of AR (AR-V7) that lack the ligand binding domain, as well as overexpressed full length AR, are known to strongly support growth of castration resistant prostate cancer (CRPC). In our first approach to develop small molecule drugs for prostate cancer, we showed that both wtAR and AR-V7 synergize with ELK1 by coopting the two ERK docking sites on ELK1, independent of the classical mechanism of (transient) activation of ELK1 via phosphorylation by ERK. As the association of ELK1 and AR is only required for prostate tumor growth, disrupting this interaction should selectively inhibit the growth of CRPC cells without interfering with the physiological role of androgen in normal tissues. Therefore, small molecules that disrupt binding of AR to ELK1 should inhibit the growth of a broader spectrum of advanced prostate tumors than androgen ablation or conventional anti-androgen therapies without the many acute and chronic side effects associated with those treatments. We have developed and conducted a stringent in situ high throughput screen for small molecules that selectively disrupt the ELK1-AR synergy. We initially screened over 18,000 compounds from diversity sets that follow the Lipinski guidelines for “drug-likeliness”. Our top hit from the screen inhibited ELK1-dependent promoter activation by androgen in a dose-dependent manner but did not inhibit promoter activation via canonical androgen response elements. Follow up structure-activity studies identified a lead compound that was much more stable than the initial hit. We report discovery of this small molecule (KCI807) that selectively disrupts ELK1-dependent promoter activation by wild-type and variant forms of AR without interfering with ELK1 activation by ERK. KCI807 has an obligatory flavone scaffold and functional hydroxyl… Advisors/Committee Members: Manohar Ratnam.

Subjects/Keywords: Oncology

Record DetailsSimilar RecordsGoogle PlusoneFacebookTwitterCiteULikeMendeleyreddit

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Rosati, R. (2017). New Mechanism Based Approaches For Treating Prostate Cancer. (Doctoral Dissertation). Wayne State University. Retrieved from https://digitalcommons.wayne.edu/oa_dissertations/1865

Chicago Manual of Style (16th Edition):

Rosati, Rayna. “New Mechanism Based Approaches For Treating Prostate Cancer.” 2017. Doctoral Dissertation, Wayne State University. Accessed July 17, 2019. https://digitalcommons.wayne.edu/oa_dissertations/1865.

MLA Handbook (7th Edition):

Rosati, Rayna. “New Mechanism Based Approaches For Treating Prostate Cancer.” 2017. Web. 17 Jul 2019.

Vancouver:

Rosati R. New Mechanism Based Approaches For Treating Prostate Cancer. [Internet] [Doctoral dissertation]. Wayne State University; 2017. [cited 2019 Jul 17]. Available from: https://digitalcommons.wayne.edu/oa_dissertations/1865.

Council of Science Editors:

Rosati R. New Mechanism Based Approaches For Treating Prostate Cancer. [Doctoral Dissertation]. Wayne State University; 2017. Available from: https://digitalcommons.wayne.edu/oa_dissertations/1865

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