JNK2 inhibits luminal cell commitment in normal mammary glands and tumors

dc.contributor.advisorVan Den Berg, Carla
dc.creatorCantrell, Michael Andrewen
dc.date.accessioned2015-08-12T18:49:43Zen
dc.date.issued2013-05en
dc.date.submittedMay 2013en
dc.date.updated2015-08-12T18:49:43Zen
dc.descriptiontexten
dc.description.abstractBreast cancer is a heterogeneous disease with vastly different tumor progression kinetics and survival outcomes depending upon the differentiation state and gene expression patterns of the tumor. Effective treatments exist for patients with endocrine therapy sensitive or HER2 overexpressing tumors, but targeted treatments are not available for other tumor types. The mechanisms governing mammary tumor phenotype generation could prove critical to finding treatments. The c-Jun N-terminal kinase (JNK) pathway has recently been implicated in the inhibition of breast tumor luminal differentiation (1, 2) and JNK2, in particular, is important in mammary tumorigenesis and tumor progression (3-8). Therefore, the involvement of JNK2 in inhibition of mammary luminal cell differentiation was investigated in normal glands and tumors. Studies found that JNK2 inhibits luminal cell populations in normal mammary ducts. Additionally, JNK2 suppresses Notch activity in stem cell niche of the developing mammary gland. In vitro assays show that control over differentiation by JNK2 is due to suppression of p53-dependent Notch1 expression. Inhibition of luminal cell populations by JNK2 is also apparent in tumor cell models regardless of p53 expression. In the p53-competent Polyoma Middle T-antigen model, Notch1 expression is suppressed by JNK2. In the absence of p53, JNK2 suppresses luminal populations independent of Notch1. In this model, decreased luminal marker expression is accompanied by increased epithelial to mesenchymal transition. It was also found that JNK2-dependent epithelial to mesenchymal transition inhibits luminal populations and is driven by JNK2-dependent suppression of Brca1. JNK2 also confers resistance to estrogen signaling inhibition, and increases the metastatic ability of tumor cells in vivo. These data establish the importance of JNK2 in mammary epithelial cell differentiation in normal glands and tumors. They also suggest that JNK2 may be an effective prognostic marker or treatment target.en
dc.description.departmentCellular and Molecular Biology
dc.format.mimetypeapplication/pdfen
dc.identifier.urihttp://hdl.handle.net/2152/30344en
dc.subjectBreast canceren
dc.subjectNotchen
dc.subjectNotch1en
dc.subjectP53en
dc.subjectBRCA1en
dc.subjectJNKen
dc.subjectJNK2en
dc.subjectMammaryen
dc.subjectEMTen
dc.titleJNK2 inhibits luminal cell commitment in normal mammary glands and tumorsen
dc.typeThesisen
thesis.degree.departmentCellular and Molecular Biologyen
thesis.degree.disciplineCellular and Molecular Biologyen
thesis.degree.grantorThe University of Texas at Austinen
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen
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