Targeting Transcription Elongation Machinery for Breast Cancer Therapy
Abstract
Alterations in gene expression, caused by mutations in various signaling pathways, lie in the heart of breast cancer development and progression. Although this has been known for many years, the general transcription machineries have never been considered good targets for cancer therapy because they are thought to be generally required for the survival of all cells. Thus, our recent finding that the transcription elongation machinery is linked specifically to breast cancer metastasis and malignant progression comes as a surprise. This new finding shows that targeting transcription events may be a highly promising direction for metastatic breast cancer therapy. Gene transcription can be regulated at two steps: transcription initiation and transcription elongation. For the last 30 years, the transcription field has been preoccupied with transcription initiation and ignored the step of transcription elongation, which in recent years has been shown to be more critical for the control of cell growth, embryonic development as well as stem cell self-renewal and differentiation. Our work over the past 10 years has identified key components of the transcription elongation machinery and shown that they play critical roles in many pathological conditions such as HIV infection. Our latest finding suggests that by aberrantly activating the transcription elongation machinery, non-invasive breast cancer cells are induced to undergo a process called epithelial-to-mesenchymal transdifferentiation (EMT) that may be necessary for cancer stem cell expansion and malignant progression. These cells also showed increased invasion and metastasized to the lung in xenograft mouse models. In human breast cancer samples, we also found that downregulation of a negative regulator of the elongation machinery correlates with increased metastasis and decreased patient survival. Based on these preliminary data, we propose to focus on the important but understudied role of transcription elongation machinery in human breast cancer progression and is designed to test the hypothesis that the transcription elongation complex plays a critical role in regulating breast cancer EMT, stemness, invasion, and metastasis through controlling the expression of essential EMT and metastasis regulators and that targeting P-TEFb may be a viable therapeutic approach to halt breast cancer metastasis. Our proposed research addresses two of the overarching challenges: (1) identify why some breast cancers become life-threatening metastasis; and (2) eliminate the mortality associated with metastatic breast cancer. This is a major advance beyond the current anti-breast cancer strategies in that transcription elongation control is an understudied area in breast cancer and its potential as a target for metastatic breast cancer treatment has not been appreciated. These studies can potentially establish the elongation machinery as a key target for breast cancer therapy. In light of the finding that two inhibitors targeting a key component of the transcription elongation complexes, flavopiridol and CYC202 (R-Roscovitine), display powerful anti-tumor effects especially against metastatic breast cancer through efficiently inducing apoptosis, our study may have immediate clinical impact on metastatic breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510067
Entities
People
- Qiang Zhou
Organizations
- United States Army
- University of California, Berkeley