GSBS Dissertations and Theses

ORCID ID

0000-0002-7267-5950

Approval Date

3-8-2018

Document Type

Doctoral Dissertation

Academic Program

Cancer Biology

Department

Program in Molecular Medicine

First Thesis Advisor

Roger J. Davis

Keywords

JNK, breast cancer, apoptosis, anoikis, mammary gland, BH3-only protein, BIM, BMF, AP1, involution

Abstract

The cJUN NH2-terminal kinase (JNK) pathway responds to environmental stresses and participates in many cellular processes, including cell death, survival, proliferation, migration, and genome maintenance. Importantly, genes that encode components of the JNK signaling pathway are frequently mutated in human breast cancer, but the functional consequence of these mutations in mammary carcinogenesis is unclear.

Anoikis – suspension-induced apoptosis – has been implicated in oncogenic transformation and tumor cell metastasis. Anoikis also contributes to lumen formation during mammary gland development and epithelial cell clearance during post-lactational involution. JNK is known to contribute to certain forms of cell death, but the role of JNK during anoikis was unclear. I examined the requirement of JNK in anoikis and discovered that JNK promotes cell death by transcriptional and post-translational regulation of pro-apoptotic BH3-only proteins. This conclusion suggested that JNK signaling may contribute to mammary gland remodeling during involution. Indeed, JNK deficiency in mammary epithelial cells disrupted the remodeling program of gene expression and delayed involution. Finally, I sought to understand the importance of JNK in mammary carcinogenesis. I found that JNK loss in the mammary epithelium was sufficient for genomic instability and tumor formation. Moreover, JNK loss in a model of breast cancer resulted in significantly accelerated tumor development. Collectively, these studies advance our understanding of the JNK pathway and breast biology, and provide insight that informs the design of therapeutic approaches that target the JNK signal transduction pathway.

DOI

10.13028/M2FH6M

Rights and Permissions

Licensed under a Creative Commons license

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Available for download on Thursday, March 14, 2019

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