MOLECULAR REGULATORS OF MAMMARY GLAND DEVELOPMENT AND BREAST CANCER PROGRESSION

Abstract

Mammary gland development is governed by a complex network of cell lineage regulators that precisely control differentiation and maintain tissue homeostasis. It is of crucial importance to understand the functions of these determinants of cellular hierarchy, as their deregulation is closely associated with cancer progression and metastasis. In this present dissertation, combining molecular biology and animal models, I provide in-depth analysis of two important regulators of both mammary gland development and breast cancer progression, with particular focuses on their functions in epithelial-mesenchymal transition (EMT) and metastasis.

The first study aimed to investigate the function of a hotspot splice site mutation in GATA3, a critical transcription factor that regulates mammary gland morphogenesis and inhibits cancer metastasis. Contrary to the common view that GATA3 mutations function by abolishing tumor suppressive functions of GATA3, I showed that this mutation created a truncated GATA3 protein that exhibits greater stability and oncogenic gain of functions. Utilizing a series of in vitro and in vivo models, I found that expression of mutant GATA3 leads to increased cell invasion and metastatic capabilities. Mechanistically, mutant GATA3 directly upregulates EMT inducer Tcf4 and promotes EMT to enable an invasive phenotype. This study demonstrated that mutation in a tumor suppressor gene can confer oncogenic functions. It also shed light on potential prognostic marker and therapeutic strategies for luminal breast cancer patients.

In the second study, I employed different genetic mouse models to investigate the functions of miR-200, an important regulator of EMT and cell stemness, in both normal and cancerous conditions in vivo. I demonstrated that, miR-200 depletion leads to impaired mammary morphogenesis exemplified by reduced ductal elongation and branching. During breast cancer progression, miR-200 strongly enhances metastatic colonization by promoting epithelialization of tumor cells at distant organs and activating EGFR and FAK signaling. Our results provided new insights into the functions of miR-200 family in normal mammary development and breast cancer progression. Collectively, these studies also suggested that both EMT and its reverse process mesenchymal-epithelial transition (MET) play critical roles during metastatic progression.