D. Craig Allred, MD

2008-2009 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 into the normal breast 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 the Allred laboratory comparing human DCIS and IBCs have identified a large number of genes that differ and he proposes that some of these differences may facilitate the development of IBC. A surprising number of these genes are present in supporting stromal cells located adjacent to tumor cells, and understanding how they contribute to IBC will be difficult without studying intact systems that include both types of cells.

The researchers have also recently developed strategies to grow human DCIS (including tumor and stromal cells) in the breast tissue of laboratory models, and these are promising new tools to study the progression of DCIS to IBC. The goal of these proposed studies is to genetically engineer some of the changes observed in the researchers' microarray studies into the tumor and stromal cells of they 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:
Apocrine metaplasia (APOM) is very common transformation which occurs in normal breast epithelium. There is compelling evidence that APOM is an evolutionary ancient innate stress response, or protective response, against environment hazards such as fluid loss and infections (viral and bacterial). One of the outcomes of APOM in normal breast cells is that estrogen receptor (ER) expression is entirely turned off, which is probably part of the protective mechanism (e.g. it may suppress proliferation in damaged cells). The original hypothesis of this study is that ER positive breast cancers may also undergo APOM, which transforms them into ER-negative breast cancers, which are more aggressive and difficult to treat. Consistent with this hypothesis, microarray studies in this project clearly demonstrated that many genetic changes associated with normal APOM are also present exclusively in ER-negative breast cancers (accounting for about a third of all ER-negative tumors).

Surprisingly, Dr. Allred’s group also showed that APOM ER-negative breast cancers have a lot in common with ER-positive breast cancers in terms of gene expression profiles, which is also consistent with our original hypothesis that APOM induces a potentially reversible transition from ER-positive to ER-negative disease, which was the long-term goal of this these studies. However, the resaerchers are at a point where they cannot pursue these studies further until a cell-line or laboratory model of inducible APOM becomes available. They tried but failed (so far) in developing such a model, despite many attempts as described in previous progress reports. Thus, the project is being discontinued, and the remaining funds are being returned to the BCRF. We thank BCRF for supporting this project, which we still find fascinating, and potentially very important clinically if APOM ER-negative breast cancers can indeed be induced to re-express ER and thereby rendered responsive to hormonal therapies. We will remain vigilant and test new strategies outside the scope of BCRF if and when a model is developed. Finally, we have a draft manuscript of our studies nearly finished, and will submit it for publication within the next few months. Hopefully, it will stimulate interest in other investigators who will also help push this forward.

Dr. Allred's new studies were designed to identify genetic alternations involved in the progression of DCIS, which is non-lethal, to invasive breast cancer (IBC), which is potentially lethal. Identifying the genes involved is the first step. In previous microarray studies comparing gene expression in human DCIS vs IBC, the researchers identified 10 genes turned off in IBC, suggesting that they may have tumor suppression function. During past months, they turned these 10 genes off in a human DCIS cell line, to test the hypothesis that they suppress invasion. Four of the genes showed behavior in cell culture suggesting that they are important in the progression of DCIS to IBC. They were also studied in a xeograft model of DCIS, and two resulted in the rapid progression to IBC—strong evidence that the normal function of these genes is to protect against tumor invasion. If this exciting preliminary data can be confirmed, it will help tremendously in designing a therapy to prevent DCIS from progressing to IBC in patients. These therapies may also be beneficial in suppressing invasion in patients who already have IBC.

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.