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Genome-wide analysis of therapeutic response uncovers molecular pathways governing tamoxifen resistance in ER+ breast cancer
Descriptive
TitleInfo
Title
Genome-wide analysis of therapeutic response uncovers molecular pathways governing tamoxifen resistance in ER+ breast cancer
Name
(type = personal)
NamePart
(type = family)
Rahem
NamePart
(type = given)
Sarra
NamePart
(type = date)
1984
DisplayForm
Rahem, Sarra, 1984-
Role
RoleTerm
(authority = RULIB);
(type = text)
author
Name
(type = personal)
NamePart
(type = family)
Mitrofanova
NamePart
(type = given)
Antonina
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Antonina Mitrofanova
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
chair
Name
(type = personal)
NamePart
(type = family)
Srinivasan
NamePart
(type = given)
Shankar
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Shankar Srinivasan
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Coffman
NamePart
(type = given)
Frederick
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Frederick Coffman
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
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NamePart
Rutgers University
Role
RoleTerm
(authority = RULIB)
degree grantor
Name
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NamePart
School of Health Professions
Role
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school
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Text
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theses
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2020
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2020-08
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(type = text)
English
Abstract
Despite recent advances in diagnosis, classification, and therapeutic management, breast cancer (BC) remains one of the leading causes of cancer-related death in women worldwide. Nearly 70% of all diagnosed cases of breast tumors are Estrogen Receptor positive (ER+) and thus anti-estrogen therapy, such as tamoxifen, has become the standard-of-care for patients with ER+ breast cancers. Yet, nearly 30% of patients treated with tamoxifen develop resistance, ultimately leading to metastasis and lethality. Prioritization of breast cancer patients based on the risk of resistance to tamoxifen plays a significant role in personalized therapeutic planning and improving disease course and outcomes. In this work, we demonstrate that a genome-wide pathway-centric computational framework elucidates molecular pathways as markers of tamoxifen resistance in ER+ breast cancer patients. Through the association of pathway activity and response to tamoxifen, we identified five biological pathways and demonstrated their ability to predict the risk of tamoxifen resistance in two independent patient cohorts (Test cohort1: log-rank p-value = 0.02, adjusted HR = 3.11; Test cohort2: log-rank p-value = 0.01, adjusted HR = 4.24). Importantly, as a negative control, we have demonstrated that the identified 5 candidate pathways did not classify patients simply based on the disease aggressiveness and that pathways of aggressiveness do not overlap with the 5 candidate pathways. Finally, we have compared our pathway signature to other known signatures of tamoxifen response and have shown superiority of our pathway-based approach (adjusted hazard ratio = 3.11, hazard p-value=0.0278). Thus, we propose that the identified pathways as well as their representative read-out-genes can be utilized to prioritize patients who would benefit from tamoxifen treatment and patients at risk of tamoxifen resistance that should be offered alternative regimens.
Subject
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Topic
Biomedical Informatics
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Title
Rutgers University Electronic Theses and Dissertations
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ETD
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ETD_11082
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application/pdf
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text/xml
Extent
1 online resource (ix, 54 pages)
Note
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Ph.D.
Note
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Includes bibliographical references
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Title
School of Health Professions ETD Collection
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rucore10007400001
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NjNbRU
Identifier
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doi:10.7282/t3-pcsy-s506
Genre
(authority = ExL-Esploro)
ETD doctoral
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Rights
RightsDeclaration
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The author owns the copyright to this work.
RightsHolder
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Name
FamilyName
Rahem
GivenName
Sarra
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime
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2020-08-10 03:41:43
AssociatedEntity
Name
Sarra Rahem
Role
Copyright holder
Affiliation
Rutgers University. School of Health Professions
AssociatedObject
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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Embargo
DateTime
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2020-08-31
DateTime
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2021-03-02
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after March 2nd, 2021.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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2020-08-18T14:29:36
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2020-08-18T14:29:36
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