New Insight into Ductal Carcinoma in Situ
Behind the Cancer Headlines®
New research conducted at the
"The implication of these studies and others is that the genetic code for breast cancer is probably written at the pre-cancerous stage, so the rest is predestined," said Robert D. Cardiff, professor of pathology and director of the Mutant Mouse Pathology Lab at the UC Davis Center for Comparative Medicine. "This has profound implications for the prevention and treatment of breast cancer."
The conventional belief has been that DCIS, the most common form of localized breast cancer, spreads beyond the milk duct only if the DCIS cells are subjected to additional genetic damage. The newer hypothesis argues that breast cancer progenitor cells are present from the beginning in precancerous lesions, and are genetically programmed to progress not only to DCIS but also right on through to invasive breast cancer.
The UC Davis findings are based on studies in a line of transgenic mice engineered to develop mammary intraepithelial neoplasia, or MIN, the mouse equivalent of human DCIS.
"The new hypothesis suggests that we are treating the
wrong breast cancer cells,"
At the
Kermit L Carraway III, an associate professor of biochemistry and molecular medicine at UC Davis Cancer Center, reported his research into the role of a substance known as Nrdp1 in the path toward malignancy. Carraway's team discovered that when mouse and human breast cancer cells have excess Nrdp1, the levels of a growth factor known as ErbB3 drop, inhibiting the cancer cells' growth and motility. The same happens in mouse breast cancer cells with excess ErbB2. The growth factor ErbB2 is the mouse counterpart of the human growth factor HER2, which is implicated in a quarter of human breast cancers. The findings suggest Nrdp1 may have a role in the treatment of HER2-positive human breast cancers.
A second team reported that the seemingly inexorable progression of MIN cells towards mammary cancer could be halted in some cases. The team, led by Lawrence Young, a senior research associate in the Center for Comparative Medicine, and Jeff Gregg, an associate professor of pathology, found that the antibiotic rapamycin quickly induced apoptosis, or rapid cell death, in some but not all MIN cell lines. The researchers' next step will be to use micro-array genetic analysis to determine which genes were expressed in the surviving malignant cells. Such genes could be promising targets for drug development.
A third team presented work suggesting that diuretics may have therapeutic potential in DCIS. Steven Anderson, an associate researcher in physiology and membrane biology, and Peter Cala, professor and chair of physiology and membrane biology, have conducted specializing imaging studies to demonstrate that MIN cells rely on a molecule known as the sodium/hydrogen exchanger to maintain a favorable pH balance within the milk ducts. Diuretics inhibit sodium/hydrogen exchange, resulting in an acidic micro-environment that is lethal to cancer cells.
"This study has potential to provide innovative new treatments for high-risk women with DCIS," Cala said.
A fourth team reported on a novel method of determining which genes confer malignancy in breast cancer. Patrizia Damonte, a researcher in the UC Davis Center for Comparative Medicine, and Alexander Borowsky, an assistant professor of pathology, have separated MIN lesions into individual cells, cultured each cell into a multicellular clump and observed each clump to see which developed into cancer. They are now analyzing the genetic makeup of the malignant clumps.
SOURCES:
Annual Meeting of the International Association for Breast
Cancer Research, September 2006,