A recent discovery by a team of researchers from the BC Cancer Agency and the Indianapolis School of Medicine in the U.S. is causing scientists to rethink how breast cancer develops.
The team has discovered normal cells with faulty telomeres, or chromosome ends.
“We are used to seeing such short telomeres almost exclusively in cancer cells armed with complex molecular machinery to survive short telomeres,” Dr. Raj Kannan said. “But here is a normal cell isolated from a healthy woman, and it contains these short telomeres.”
The cells are a type of cell researchers call “luminal progenitors.” There are other progenitor cells — a type of cell that can form one or more different kinds of cells — in the breast that don’t have the flawed telomeres.
Typically, in healthy cells with critically short telomeres, the dysfunctional telomeres trigger DNA damage in cells. Healthy cells are forced to molecularly compensate for this telomere crisis. When they under-compensate, they typically die or stop dividing. When they overcompensate, they generate what Kannan calls “immortal malignant clones.”
As a notable exception, breast luminal progenitor cells have demonstrable potential to multiply in spite of flawed telomeres and DNA damage.
This makes the cell highly vulnerable to cancer-initiating mutations in the breast, Kannan says.
“They have proliferative potential, and they have dysfunctional telomeres,” he said. “It is logical to assume that these cells may act as a breeding ground or launch pad for cancer to initiate if the DNA becomes unstable because of these short telomeres.”
A researcher at the BC Cancer Agency Research Centre working in Dr. Connie Eaves’ stem cell biology laboratory, Kannan has received a Canadian Breast Cancer Foundation Fellowship and, more recently, the Mitacs Fellowship. Mitacs is a Canadian not-for-profit research organization that partners with government, companies and academia to encourage innovation.
Kannan has been with the BC Cancer Agency since moving to Vancouver from New Zealand five years ago to work under Eaves, a leader in blood and breast stem cell research.
From the Terry Fox Laboratory at the BC Cancer Agency, Eaves and her team pioneered methods to isolate single cells and separate them into different populations, and identified breast stem cells.
After 100 years of breast cancer research, scientists are still attempting to discover which cells are responsible for the disease, Kannan says, and what goes wrong with the cells that leads to cancer initiation. Isolating and separating cells brings researchers closer to this holy grail for research scientists, he says.
Understanding the various types of cells and their functions “is at the heart of what we’re trying to do in our lab,” Kannan said. “When we are able to purify various cellular compartments, we are then able to subject these cells to various functional assays.”
Breast cancer is a clonal disease, he says.
This means that cancer “starts from a single breast epithelial cell. We may have better rationale to prevent cancer if we understand which cell seeds the disease.”
At present, nothing appears certain about the potential of any cell to lead to breast cancer. Even the presence of the most-cited genetic suspect in breast cancer, the defective BRCA1 gene, although it increases cancer risk, is not a guarantee the disease will develop.
“If you get a variant copy of this gene, still it’s not 100 per cent you get breast cancer, it’s 87 per cent,” Kannan said. “There are unknowns. We are trying to identify this gap.”
Billions of cells are produced in a breast over a lifetime, making identifying the exact cause of breast cancer something like looking for a needle in a haystack.
“It’s still that one high-risk cell that is needed to cause cancer,” he said. “When every cell in that breast has BRCA1 mutation, or has inherited a mutated copy, still it is that one cell that causes cancer. That tells you every cell has different potential. How do we tell which cells lead to cancer?”
The ultimate goal of his lab and other cancer research labs is more than to discover what cells have the potential to become cancerous.
“We need to understand how cells function in the breast, and identify the state of cells prone to transforming events, which is where cancers really take off,” he said.
If those cells can be discovered and isolated, they can be targeted.
“Finding the cellular source of cancer is not the ultimate end, but will lead us into a new era in cancer prevention and treatment research. My feeling is that we have not even scraped the surface of what is possible in cancer treatment.”
Along with our understanding of breast progenitors, another recent discovery may advance breast cancer.
Working in San Francisco and Kyoto, a team led by Dr. Shinya Yamanaka successfully reprogrammed mature human skin fibroblast cells “to become unspecialized human embryo-like cells within a few weeks,” Kannan said.
These induced pluripotent stem cells (iPS cells), capable of making all human body parts, are now derived from various types of mature cells in our bodies.
These embryo-like cells are capable of making all human body parts.
“Muscle, bone, blood — all those very complex tissues can be derived from skin. The potential that every cell carries is incredible and humbling.”
The discovery means that “it is not unthinkable that breast cancer cells could be developmentally re-wired to behave normally with no side-effects,” Kannan said.
By isolating more and different kinds of cells, Kannan says he is hopeful we’ll soon be able to “coerce immortal breast cancer stem cell clones to differentiate into normal cells with limited lifespan.”
The more research there is in this area, the faster we may get there, he says.
“Every researcher has his or her view of how cancers arise and progress, and they go after it and try to find ways to manage it,” he said. “Not every approach is successful. There are a lot of failures in research. We learn from those failures and learn from each other’s research. Once in a while you come across these findings that totally change the field, that change the way you look at the disease.”