Breast cancer has been one of the hottest fields of scientific research for more than 50 years now, with widely recognized public campaigns to increase awareness and education. These combined efforts have led to much improved survival outcomes during this time. The five-year survival for earliest stages is close to 100 percent, 93 percent for the second earliest stage (2), and 72 percent for stage 3.
Kaitlyn Dvorak stands by a research poster describing the work she has done with trying to determine the role microenvironment plays in cancer progression.
Despite these new advances in early stage breast cancer, approximately 41,000 breast cancer patients were predicted to die in the United States this past year. These deaths are due to stage 4 cases, which usually include metastatic breast cancer.
Metastatic breast cancer is when cancer cells from the primary tumor enter the blood or lymph circulation system of the body and travel to distance sites to grow secondary tumors. This late-stage breast cancer usually has a poor outcome with a five-year survival of only 22 percent. Standard treatments for breast cancer at earlier stages are less effective against this late-stage metastatic disease, which motivated our lab to identify mechanisms to stop metastatic breast cancer.
Research goals for breast cancer research have been focused on figuring out different roles of DNA mutations, heredity, and hormones for predicting and treating this disease. We focused on the breast cancer cells.
In recent years, research questions began to include different surrounding cells and tissues for possible roles in the growth of breast cancer. This closely surrounding area, called the microenvironment, can take on some features similar to the cancer cells, creating a population of cells that are not fully cancerous but are also not quite normal. This microenvironment can release molecular factors that can increase tumor cell growth, supply nutrients to the tumor, and even increase cell movement — possibly increasing metastatic travel of breast cancer.
Our overall goal is to understand what drives cancer cells to move to other body sites. Breast tissue is composed of many different types of cells and structures which metastatic cancer cells must travel through to reach their new metastatic site before lodging and growing.
Much like our own skeleton, the cytoskeleton provides support for each of our cells. To travel successfully, a cancer cell must continually change its cytoskeleton, which is not set in a permanent position like our human skeleton.
A cell can alter each part of its cytoskeletal structure that is required for cell movement through specific tissue, and when that structure isn’t needed anymore, it is broken down. Specific proteins are required in the formation and retraction of each of these different cytoskeletal structures.
Our research is focused on how these structures can change. We now know that a protein called mDia2 is an important regulator of the cell cytoskeleton. The mDia2 protein helps to build and control cell structures required for moving through different microenvironments in the tissue.
One important question of our research group is to figure out if other cells in the local microenvironment can affect expression of mDia2 in breast cancer cells. In other words, does the microenvironment help control cancer cell movement by affecting regulators, such as mDia2, of the cancer cell cytoskeleton?
When we grow these other cells from the microenvironment in a special media in our laboratory, these cells release molecular factors into the media. This conditioned media is then used to replace the media that breast cancer cells grow in. This media switch allows us to examine what effects the conditioned media from noncancer cells has on breast cancer cells.
Indeed, when we add this conditioned media to breast cancer cells, we see increased cancer cell movement.
We can also use special plating conditions to grow these breast cancer cells into small clusters of cancer cells that are like a tumor. This allows us to investigate growth of cancer cells in a three dimensional way that is similar to tumors in patients, rather than just one layer of cells on a culture plate.
We now know that the cancer cell clusters also have increased movement through a surrounding matrix similar to our body’s tissues. Cancer cells in the body must travel through such tissues to metastasize. These results show us that conditioned media from other cells in the microenvironment can indeed drive breast cancer cells to more movement.
Next we asked if increased cancer cell movement was due to changes in the cytoskeleton. We looked at the cytoskeletal regulator mDia2 in breast cancer cells that had been treated with the conditioned media. We observed that this exposure caused expression of mDia2 to be lost and, most importantly, the breast cancer cells grew more slowly.
These results might seem like the opposite of increasing cell movement, however decreasing growth of breast cancer cells is known as “go versus grow.” This means cells that are moving are less likely to grow.
We believe that by carefully investigating the microenvironment around tumors, there is an opportunity to determine the possibility of metastasis. This knowledge will help to guide better treatment options.
Kaitlyn Dvorak earned her PhD in the University of Toledo College of Medicine and Life Sciences Biomedical Science Program this spring. She did her doctoral research in the laboratory of Dr. Kathryn Eisenmann in the Department of Cancer Biology. For more information, contact Kaitlyn.Dvorak@rockets.utoledo.edu or go to utoledo.edu/med/grad/biomedical.
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