Mien-Chie Hung, PhD

2012-2013 BCRF Project:
Co-Investigator: Gabriel N. Hortobagyi, MD, University of Texas MD Anderson Cancer Center

Breast tumor initiating cells (or BTICs) are highly aggressive cells that are thought to be responsible for resistance to therapies. Drs. Hortobagyi and Hung have expanded on their previous findings that EZH2 can enhance the BTIC population, by exploring its mechanism of action. They found that the enzyme CDK may play a role in the EZH2’s enhancement of BTICs. In addition, they developed the expression system VISA-Claudin4-BikDD that can be used as gene therapy for breast cancer patients and are currently working towards a phase I clinical trial.

Since their previous studies on EZH2 and BikDD have attracted grants from other sources thanks to initial funding from BCRF, Drs. Hortobagyi and Hung now plan to focus on related research focusing on triple negative breast cancer/basal-like, which is a highly heterogeneous disease and shares many similar characteristics of tumor initiating cells (TICs, or cancer stem cells) particularly in its metastatic capability. In order to understand central molecular targets and signaling networks that are associated with this hard-to-treat breast cancer, this team plans to use bioinformatics in their identification of potential therapeutic targets. The first priority of their analysis will be to focus on cancer-related kinases to determine whether these kinases contribute to the cancer stem cell properties and metastatic abilities of triple negative breast cancer. Their preliminary results have given clues as to what may inhibit the cell growth and clonogenic ability of triple negative breast cancer cells, as well as what may play an integral part in triple negative breast cancer progression. If successful this new project will identify important molecular targets and signaling crosstalk, and Dr. Hortobagyi and Hung hope that the findings will be translated into clinical settings for treating triple negative breast cancer.

Mid-year Progress: Since fall, Drs. Hortobagyi and Hung have successfully identified potential critical molecular targets that may contribute to triple negative breast cancer progression. These targets may also predict outcomes of overall survival. Drs. Hortobagyi and Hung's findings provide a basis to further develop novel therapy and/or potential marker-guided clinical trials for triple negative patients.

Read more about Drs. Hortobagyi and Hung's work in Science Daily

Bio:
Dr. Mien-Chie Hung is Professor and Chair for the Department of Molecular and Cellular Oncology at the University of Texas MD Anderson Cancer Center, Houston, Texas. He received his undergraduate and graduate degrees from the National Taiwan University in Taiwan and his PhD from Brandeis University in Massachusetts. Currently, he also serves as the Director of the Breast Cancer Basic Research Program and is the Ruth Legett Jones Distinguished Chair. In addition, he is Professor, Department of Surgical Oncology, Distinguished Teaching Professor, and Director, Center for Biological Pathways.

Dr. Hung became a member of the Academia Sinica in Taiwan in July, 2002. Dr. Hung serves as a founding Editorial Members on Cancer Cell as well as an Associate Editor on Cancer Research, Clinical Cancer Research, Molecular Cancer Research and Molecular Carcinogenesis.

In recent years, Dr. Hung's laboratory has focused on signaling transduction pathways of tyrosine kinase growth factor receptors such as EGFR and HER-2/neu; molecular mechanisms of oncogenes -including transformation and tumorigenesis; and molecular mechanisms of tumor suppressor genes-mediated anti-tumor activities. His group made a critical breakthrough in showing that the transmembrane tyrosine kinase receptor EGFR can bind to a specific DNA sequence in the nucleus and that it functions as a transcription factor that can activate genes required for cell proliferation. Dr. Hung's group also demonstrated regulation of the cell cycle inhibitor p21 by the HER2/neu oncogene through phosphorylation of p21 by Akt, which results in changes in the subcellular localization.

The study provides a rationale for a long puzzling question surrounding p21--a cell cycle inhibitor that also associates with anti-apoptotic function. Furthermore, his group has demonstrated that an oncogene such as HER2/neu can suppress expression of the tumor suppressor gene p53 through the Akt/MDM2 pathways. The study provides a plausible mechanism showing that the p53 tumor suppressor gene, even without mutation, is frequently silent in oncogene-activated cancer cells such as HER-2/neu and Akt.

Most recently in the April 16th issue of Cell journal, Dr. Hung and co-workers have identified an important new tumor suppressor protein, FOXO3a (known as a longevity gene in some animal models) and a new oncogene, IKK (belongs to a family of enzymes called kinase) that provide targets for cancer therapy. Previously, these proteins had been suspected to be involved in cancer, but there was no direct evidence for that. Dr. Hung has demonstrated that IKK promotes tumorigenesis through inhibition of FOXO3a.

The other main research in Dr. Hung's laboratory is in cancer gene therapy that includes development of preclinical gene therapy animal models, including breast, ovarian and pancreatic cancers; identification of therapeutic genes suitable for cancer gene therapy; and development of gene delivery system for cancer gene therapy. Dr. Hung is the first person to demonstrate that adenovirus 5 E1A gene has anti-tumor ability in HER2/neu-over-expressing cancer cells by downregulation of HER2/neu overexpression. He is also a key person to actively drive laboratory research of E1A tumor suppressor gene into clinical trials (bench to bedside). Furthermore, Dr. Hung's laboratory is working on developing a tumor-targeted nonviral gene delivery system for human cancers such as breast, ovary, pancrease and prostate.