Year: 2017
Type: dissertation
Abstract: PTEN is one of the most frequently inactivated tumor suppressors in human malignancies including breast cancer, and its mutation or loss is often implicated in advanced cancers and therapy resistance. Yet, germline mutations in PTEN induce non-malignant hamartomas in humans and mouse tumors with a wide spectrum of aggressiveness, indicating context-dependent effects. To develop effective anti-cancer therapies, a better understanding of how mutational events cooperate with PTEN-loss is required. In this thesis, I show that most tumors derived from Pten-deleted mammary epithelium were highly differentiated and lacked transplantable tumor initiating cells following FACS isolation or transient propagation under non-adherent conditions. Surprisingly, a rare group of Pten-deficient tumors with distinct histology did contain transplantable TICs. In comparing these two tumor groups, I identified low miR-143/145 expression as a critical factor that determined transplantability. Knockdown of miR-143/145 in Pten-deficient tumor cells promoted secondary tumor engraftment, RAS pathway activation and sensitivity to MEK inhibitors. In basal-like breast cancer, 7% showed combined loss of PTEN and miR-145 as well as poor clinical outcomes. Thus, Pten loss can initiate benign or aggressive mammary tumors depending on miR-143/145 status. Patients with basal-like tumors and low-Pten/miR-143/145 expression should be identified and prioritized for aggressive therapy. Pten-deletion also cooperated with p53R270H mutation, resulting in diverse tumors including basal-like and claudin-low. Compared to mammary tumors arising from Ptenf:p53f mice, Ptenf:p53R270H mammary tumors were more capable of undergoing mesenchymal-epithelial transition (MET) and possessed greater metastatic potential. Together, these findings identified important oncogenic events that cooperate with PTEN-loss to induce aggressive breast cancer, enhance metastatic progression and influence response to therapy, and have significant implications for personalized breast cancer treatment.
Source: TSpace (University of Toronto)
Author: Sharon Wang
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2899598716