Advisory Committee Chair
Rajeev Samant
Advisory Committee Members
Robert A Kesterson
Eddy Yang
Etty Benveniste
Lalita Shevde-Samant
Document Type
Dissertation
Date of Award
2017
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Distant metastasis of breast carcinoma reduces the five year survival rate of patients from 90% to a dismal 25%. Although the metastatic cascade has been extensively studied for decades, players that influence the progression of metastatic disease remain elusive. N-MYC and STAT Interactor (NMI) is a gene previously demonstrated by Devine et. al. to be downregulated with metastatic progression of breast cancer. However, due to the lack of a relevant genetic model, details of biological consequence of the loss of expression of this gene were unknown. We have constructed and characterized a mammary specific Nmi knock out mouse to elucidate additional pathways that can be targeted. The functional consequence of Nmi loss on epithelial morphology and invasion was strongly exemplified in our mammary specific knock out models including a carcinogen-induced and oncogene-driven tumor model. Specifically, Nmi knock out mammary epithelial and tumor cells showed invasive morphological characteristics when grown in two-dimensional as well as three-dimensional culture. In vivo, these cells also exhibited deficiencies in luminal differentiation due to activated Wnt/b-catenin signaling, a pathway necessary for maintenance of stem and progenitor mammary epithelial populations. These phenotypic and signaling alterations culminated in enhanced metastatic ability of Nmi knock out tumors in both models, thereby confirming our hypothesis that Nmi loss results in increased metastasis. In patients, the exact etiology of NMI loss was not known. We identified the microRNA-29 family as an upstream regulator of NMI in human breast cancer cell lines and patient specimens. Moreover, in the context of NMI expression, miR-29 up-regulation also induces a loss of epithelial phenotype, and a gain of invasive characteristics similar to our models. Interestingly, mir-29 down-regulation of NMI also activated Wnt signaling in breast cancer cell lines. Overall, our work shows that in breast cancer, Wnt signaling stimulates the expression of the miR-29 family, which in turn is capable of downregulating NMI levels. Furthermore, Nmi downregulation leads to an inhibition of luminal differentiation concomitant with a gain in invasive morphology and further activation of Wnt/b-catenin signaling. Ultimately, our models show that the functional consequence of Nmi loss in mammary tumors is enhanced metastatic capability.
Recommended Citation
Pruitt, Hawley Christine, "Elucidating the Physiologic and Prognostic Significance of N-Myc and STAT Interactor using Models of Mammary Development and Metastasis" (2017). All ETDs from UAB. 2756.
https://digitalcommons.library.uab.edu/etd-collection/2756