Finding a fingerprint for an invasive cancer still in hiding

Biomarkers help detect cancer in its earliest stages, or sometimes before it shows up at all, making it particularly useful in early stage breast cancer diagnosis that can sometimes progress rapidly or lay dormant.

Fariba Behbod, Pharm.D., Ph.D., a member of the Cancer Prevention Program at The University of Kansas Cancer Center and associate professor of cancer and developmental biology, wants to make it easier to determine which patients will develop aggressive breast cancer.

Ductal carcinoma in situ (DCIS) is a type of noninvasive disease that can eventually become an invasive type of breast cancer. In most cases, there is no noticeable tumor, and the disease is usually diagnosed by a mammogram.

"A biomarker that can identify DCIS patients who are not at risk for subsequent invasion could save many lives and keep women from having to go through medical and surgical therapy," said Dr. Behbod.

It is difficult to tell which patients with ductal carcinoma in situ will get an invasive cancer, and patients must be closely monitored or have preemptive treatment. Currently, women either have a lumpectomy, mastectomy or chemotherapy and radiation; however, these treatments may be too invasive and costly for those who do not necessarily need it right away.

Dr. Behbod's ultimate goal is to determine the best ways to diagnose and treat DCIS based on solid molecular-based evidence. The potential biomarker her team is studying is a gene called BCL9. This gene was chosen because it's shown to play a role in the progression of other types of cancer. Dr. Behbod believes it also plays a role in invasive transition of ductal carcinoma in situ.

Based on two key behaviors BCL9 has shown in other cancers, Dr. Behbod is hypothesizing that the gene creates a microenvironment where invasive tumors can thrive. The first is BCL9's relationship with the Wnt signaling pathway. This pathway was discovered as a proto-oncogene (a normal gene that could become an oncogene after mutations or amplified expression) in breast cancer research on mice. The Wnt pathway tells cells to multiply -- and uncontrolled rapidly dividing cells is the beginning of cancer. Dr. Behbod believes that BCL9 encourages and enhances this pathway in DCIS tissue.

"When we lowered the expression of BCL9 in our models, the progression of the cancer slowed," said Dr. Behbod.

BCL9 also promotes invasive tumor growth by "recruiting stromal macrophages to DCIS," said Dr. Behbod. Macrophages are a type of white blood cell that eat up foreign substances and cell debris. They add to tumor growth by gravitating towards dying tumor cells, which promotes chronic inflammation.

Proving that BCL9 does contribute to these behaviors would mean BCL9 is likely a biomarker for DCIS breast cancer that will eventually become invasive.

To study DCIS, Dr. Behbod, developed an in-vivo DCIS model called MIND (mouse intraductal). The MIND model has the ability to mimic breast cancer progression from start to finish, tracking the cells as they leave the in-situ microenvironment and invade the surrounding breast tissue. Being able to track the progression in real time allows Dr. Behbod's team to do molecular profiling, showing the increased presence of BCL9 and leading to Dr. Behbod's current research work.

"The gene expression changes over time in the breast cells as well as the surrounding breast tissues as the breast cancer goes from non-invasive to invasive," said Dr. Behbod. "That's why we're zeroing in on this particular gene; BCL9 may play a dual role in the breast cancer cells and in recruiting stromal macrophages.

If BCL9 is a biomarker for DCIS progressing into an invasive cancer, it would be easier to figure out who those high-risk patients are. It would also allow more research into finding a drug target for BCL9 to treat those with a future risk for developing invasive cancers.

To study BCL9's role as a biomarker of high risk DCIS and as a potential drug target, Dr. Behbod has received awards from the National Cancer Institute and the Breast Cancer Research Foundation-American Association for Cancer Research in 2014.

"Because it seems this gene is involved in the more aggressive progression of DCIS and is linked to a poor prognosis, it's our hope that this BCL9 is a biomarker and we can find therapies to treat this type of breast cancer earlier," said Dr. Behbod.