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Protein Interactors Alter Progestero...

University of Kansas., Cancer Biology.

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Protein Interactors Alter Progesterone Receptor (PR) Transcriptional Programs and Oncogenic Potential in Breast Cancer.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Protein Interactors Alter Progesterone Receptor (PR) Transcriptional Programs and Oncogenic Potential in Breast Cancer./
Author:	Holloran, Sean Matthew.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
Description:	126 p.
Notes:	Source: Dissertations Abstracts International, Volume: 83-03, Section: B.
Contained By:	Dissertations Abstracts International83-03B.
Subject:	Molecular biology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28644924
ISBN:	9798535575001

Protein Interactors Alter Progesterone Receptor (PR) Transcriptional Programs and Oncogenic Potential in Breast Cancer.
Holloran, Sean Matthew.

Protein Interactors Alter Progesterone Receptor (PR) Transcriptional Programs and Oncogenic Potential in Breast Cancer. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 126 p.

Source: Dissertations Abstracts International, Volume: 83-03, Section: B.

Thesis (Ph.D.)--University of Kansas, 2021.

This item must not be sold to any third party vendors.

Breast cancer is the second leading cause of cancer-related death among women in the United States. Upon diagnosis most breast cancers are diagnosed as hormone receptor (HR) positive. HR-positive tumors are classified by their expression of estrogen receptor (ER) and progesterone receptor (PR). ER signaling has been the primary focus of targeted therapies for HR-positive breast cancer. Standard of care for treatment of HR-positive breast cancer is to target ER/estrogen. Though these treatments have initial efficacy in most women with HR-positive breast cancer, many women will eventually relapse on these therapies. Thus, underscoring the clinical need for new, non-ER/estrogen-based treatments. The study of PR in breast cancer development and progression is not well understood. PR is a ligand-activated nuclear receptor that transcriptionally regulates a large repertoire of genes involved in cell cycle, growth, proliferation, and survival. PR/progesterone regulation has been well studied, but the impacts of other hormones, proteins, and modifications on PR gene transcription have been less characterized. These studies test the hypothesis that PR co-regulators alter PR-mediated transcriptional regulation in breast cancer cells. Herein, we establish how the interaction between PR/progesterone and prolactin, KDM4B, and O-GlcNAc modification via OGT alter the PR transcriptional landscape and oncogenic potential of breast cancer. We discovered that progesterone and prolactin modulate each other's transcription, and that this prolactin alteration to PR transcription was independent of the canonical prolactin signaling protein STAT5. We also established that knockdown of KDM4B does not significantly alter PR/progestin mediated gene programs. Finally, our lab has identified that PR interacts with OGT, leading to an O-GlcNAc post-translational modification on PR at residue Ser499. We also discovered that the combination of PR, progesterone, and increased levels of O-GlcNAc have an additive effect on tumor growth. It is significant that PR is capable of interacting with a multitude of co-regulators, and that these interactions lead to different effects of PR transcriptional regulation in breast cancer. These multiple co-regulators of PR complicate the study of PR in breast cancer but understanding these PR protein-protein interactions can help us better understand how PR targeted therapies would impact the transcriptional landscape and progression of tumors.

ISBN: 9798535575001Subjects--Topical Terms:

517296
Molecular biology.
Subjects--Index Terms:

Lysine demethylase 4B (KDM4B)

Protein Interactors Alter Progesterone Receptor (PR) Transcriptional Programs and Oncogenic Potential in Breast Cancer.
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520 $a Breast cancer is the second leading cause of cancer-related death among women in the United States. Upon diagnosis most breast cancers are diagnosed as hormone receptor (HR) positive. HR-positive tumors are classified by their expression of estrogen receptor (ER) and progesterone receptor (PR). ER signaling has been the primary focus of targeted therapies for HR-positive breast cancer. Standard of care for treatment of HR-positive breast cancer is to target ER/estrogen. Though these treatments have initial efficacy in most women with HR-positive breast cancer, many women will eventually relapse on these therapies. Thus, underscoring the clinical need for new, non-ER/estrogen-based treatments. The study of PR in breast cancer development and progression is not well understood. PR is a ligand-activated nuclear receptor that transcriptionally regulates a large repertoire of genes involved in cell cycle, growth, proliferation, and survival. PR/progesterone regulation has been well studied, but the impacts of other hormones, proteins, and modifications on PR gene transcription have been less characterized. These studies test the hypothesis that PR co-regulators alter PR-mediated transcriptional regulation in breast cancer cells. Herein, we establish how the interaction between PR/progesterone and prolactin, KDM4B, and O-GlcNAc modification via OGT alter the PR transcriptional landscape and oncogenic potential of breast cancer. We discovered that progesterone and prolactin modulate each other's transcription, and that this prolactin alteration to PR transcription was independent of the canonical prolactin signaling protein STAT5. We also established that knockdown of KDM4B does not significantly alter PR/progestin mediated gene programs. Finally, our lab has identified that PR interacts with OGT, leading to an O-GlcNAc post-translational modification on PR at residue Ser499. We also discovered that the combination of PR, progesterone, and increased levels of O-GlcNAc have an additive effect on tumor growth. It is significant that PR is capable of interacting with a multitude of co-regulators, and that these interactions lead to different effects of PR transcriptional regulation in breast cancer. These multiple co-regulators of PR complicate the study of PR in breast cancer but understanding these PR protein-protein interactions can help us better understand how PR targeted therapies would impact the transcriptional landscape and progression of tumors.
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650 4 $a Cancer therapies. $3 3557730
650 4 $a Mammography. $3 832932
650 4 $a Pregnancy. $3 663805
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650 4 $a Cell cycle. $3 766119
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650 4 $a Statistical analysis. $3 3543751
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650 4 $a Hormone replacement therapy. $3 3562671
650 4 $a Hysterectomy. $3 3296701
650 4 $a Steroids. $3 697464
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653 $a Lysine demethylase 4B (KDM4B)
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653 $a Progesterone
653 $a Progesterone receptor (PR)
653 $a Prolactin
653 $a Signal transducer and activator of transcription 5 (STAT5)
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