D. Craig Allred, MD

2007-2008 BCRF Project:
Human invasive breast cancers (IBCs) are potentially lethal. They develop from pre-existing non-invasive breast cancers, referred to as ductal carcinoma in situ (DCIS), which are non-lethal. Understanding how breast cancers invade could lead to new strategies to prevent it, and success will almost certainly be based on a detailed understanding of the biological alterations responsible for invasion. Unfortunately, very little is known about these alterations.

Recent microarray experiments from Dr. Allred's laboratory comparing human DCIS and IBCs have identified a large number of genes which may be important. A surprising number of these genes are present in stromal cells adjacent to tumor cells, and understanding how they function will be difficult without studying intact systems including both types of cells. The Allred team has also recently developed strategies to grow human DCIS (including tumor and stromal cells) in the breast tissue of laboratory models, and these living models are promising new tools to study the progression of DCIS to IBC. The goal of this year's proposed studies is to genetically engineer some of the changes observed in microarray studies into the tumor and stromal cells of the researchers' DCIS models to identify which genes are involved in the progression to IBC. Identifying the genes involved in tumor invasion is an essential first step towards developing new therapeutic strategies to prevent it.

Mid-Year Progress Report:
Ductal carcinoma in situ (DCSI) is the precursor of most human invasive breast cancers (IBCs). Unlike DCIS, IBCs are potentially lethal and preventing the progression of the former to the latter would save many lives. Despite a substantial body of work, the mechanisms of progression remain unknown. Many studies have focused on assessing various biological characteristics and differences in the tumor epithelial cells of DCIS and IBCs. Surprisingly, they are very similar for nearly every feature that has been evaluated, including specific mutations and genes expression profiles assessed by microarrays (e.g. basal, luminal, and erbB2 intrinsic subtypes).

One of the most important conceptual advances in this field is the recent realization that adjacent stromal cells are being actively recruited by tumor epithelial cells to promote and sustain invasion, and understanding this process will require model systems with both compartments. Dr. Allred proposed to study this interaction using recently developed models of DCIS, developed by Dr. Allred and his collaborators (especially Dr. Dan Medina at Baylor College of Medicine), and are the first of their kind.

They currently have three established models and many more under development. In addition, they have identified a large number of differentially expressed genes between the stromal and epithelial compartments of human DCIS and IBCs in previous microarray studies. The primary aim of this proposal was to genetically engineer some of these genetic differences into the HIM models, and cultured cell lines derived from them, and determine their abilities to promote and/or suppress invasion.

Bio:
Dr. Allred is an internationally recognized expert in breast pathology and research. He has served in numerous advisory positions in government, industry, and publishing on matters of scientific policy, research, and clinical care relating to breast cancer. He has been a member of the organizing committee of the San Antonio Breast Cancer Symposium, one of the most influential scientific forums on breast diseases in the world, for over 10 years.

His research interests, supported by a variety of federal, industrial, and philanthropic grants, include: (1) the molecular basis for response and resistance to breast cancer therapy; (2) the identification of biomarkers which predict clinical outcome and response to therapy; and (3) the molecular alterations responsible for the development and progression of premalignant disease to breast cancer. Dr. Allred has authored over 180 book chapters, scientific articles, editorials, and reviews on many breast cancer-related issues.