Combined Biology and Bioinformatics Approaches to Breast Cancer
Abstract
LMO4 is highly expressed in breast epithelial cells and is related to cell proliferation and/or invasion in vivo. Because these cellular features are associated with breast carcinogenesis and since LMO4 is overexpressed in more than 50% of breast cancer cases, we hypothesize that LMO4 may play roles in oncogenesis of breast epithelial cells by regulating proliferation, invasion and/or other cellular features. Using LMO4 over-expression or shRNA expression system in vitro, I found that LMO4 play crucial roles in the regulation of cell proliferation and apoptosis of normal mammary gland epithelial cells or breast cancer cells. Furthermore, I have also observed that deletion of LMO4 impaired the function and development of mammary gland in LMO4 conditional knockout mice, indicating that LMO4 protein is necessary for maintaining the normal development of mice mammary gland. In addition, I demonstrated that the LMO4 can modulate TGF signaling and regulated the proliferative response of epithelial cells to TGF signaling, and thereby linked LMO4 to a conserved signaling pathway that plays important roles in epithelial homeostasis. Under the support of grant, I received excellent training in bioinformatics. By combining previously described functional methods with bioinformatics approaches, we used DNA microarrays to discover LMO4-responsive genes, and identified BMP7 as a key down-stream gene of LMO4. In addition, we also found a significant correlation between LMO4 and BMP7 transcript levels in a large dataset of human breast cancers, providing additional support that BMP7 is a bona fide target gene of LMO4. Finally, we demonstrated that LMO4 binds to HDAC2 and that they are recruited together to the BMP7 promoter. We also suggested a novel mechanism for LMOs; LMO4, Clim2 and HDAC2 are part of a transcriptional complex, and alterations in LMO4 levels can disrupt the complex, leading to decreased HDAC2 recruitment and increased promoter activity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2007
- Accession Number
- ADA476748
Entities
People
- Zhongxian Lu
Organizations
- University of California, Irvine