D. Craig Allred, MD

2009-2010 BCRF Project:
The overall goal of this research project is to identify genes involved in the progression of human non-invasive breast cancer (which is "harmless"), to invasive breast cancer (which is potentially lethal). During the past several months, Dr. Allred and colleagues identified three genes (CSTA, FAT1, DST) whose normal functions appear to inhibit the invasion of breast cancer cells, which they demonstrated in comprehensive studies of a non-invasive human breast cancer cell line referred to as DCIS.COM.

In a new project, they propose to continue and expand these studies by determining whether these genes have similar invasion-suppressor functions in additional noninvasive human breast cancer cell lines, which would indicate that they are also important in patients. If successful, it could lead to new therapeutic strategies to prevent the progression of non-invasive to invasive breast cancer. The scientists will also evaluate whether and how mammary stromal cells modulate the functions of these genes during tumor progression, which may also lead to new therapies to prevent it.

Finally, they will determine whether measuring the protein products of these genes is helpful in determining the likelihood that non-invasive will progress to invasive breast cancer, which could help individualize and optimize therapy in patients with noninvasive disease.

Mid-Year Progress Report:
In previous microarray studies, Dr. Allred and colleagues identified several genes expressed at different levels in clinical samples of human ductal carcinoma in situ (DCIS) compared to invasive breast cancers (IBC). Three particularly interesting genes (CSTA, FAT1, and DST) were expressed at very high levels in DCIS, but very low levels in IBC and, thus, the researchers have been studying whether they are important suppressors of tumor invasion.

Using genetic engineering, they recently inhibited the expression of these genes in a human DCIS cell line, and evaluated the effects. They observed significant increases in growth, migration, and invasion through artificial membranes of the cells grown in laboratory cultures. They also observed a dramatic increase in the progression of the cells to invasive cancers when they were grown in the ducts of mammary glands. All of these observations strongly support the hypothesis that these genes normally suppress tumor invasion.

In ongoing studies, the researchers are determining whether this is true in multiple cell lines of human DCIS. They are also evaluating whether decreased levels of protein expression in patients with DCIS are associated with an increased risk of progressing to IBC. If the studies confirm that any of these genes are indeed important in suppressing invasion, then they may be very useful as prognostic factors in patients with DCIS, and as targets for novel therapies to prevent the progression to 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.