Researchers at Dana-Farber Cancer Institute have found in a new study that cells lining milk ducts in the breast may trigger spread of a common form of breast cancer.
According to the study, when a form of cancer that begins in the milk ducts of the breast invades neighbouring tissue to spread to other parts of the body, the cause lies not in the tumour cells themselves but in a group of abnormal surrounding cells that cause the walls of the duct to deteriorate like a rusty pipe.
AdvertisementThe findings might lead to screening tests to determine whether the disease, known as ductal carcinoma in situ, or DCIS, is likely to spread beyond the ducts, based on genetic abnormalities in cells in the ducts' lining.
And the discovery also sets the stage for treatments that, by targeting these abnormalities, shore up the duct walls and keep the cancer contained.
"Women whose DCIS has invaded the ducts are known to have a greater chance of metastasis, or spreading disease. But it hasn't been clear what causes the transition from a localized cancer to invasive disease," said the study's senior author, Kornelia Polyak, MD, PhD, of Dana-Farber.
"This study demonstrates that in DCIS of the breast, and potentially in other cancers that originate in duct tissues, the answer may lie in the tumour's microenvironment -- the cells and tissue that surround the cancer," Polyak added.
For the study, Polyak and her colleagues focused on myoepithelial cells, which form part of the lining of the milk ducts and are involved in breast development, as well as impeding the growth and invasiveness of some cancer cells.
In order to study what role, if any, these cells play in DCIS, the researchers worked with a specially engineered line of cells known as MCFDCIS.
When injected in laboratory animals, the MCFDCIS cells formed DCIS-like tissue that developed into invasive tumours, providing a good model of what happens in human disease.
When researchers injected both MCFDCIS and myoepithelial cells into the mice, DCIS tumours arose, but they were confined to the ducts.
When they injected MCFDCIS cells and fibroblasts, cells found in milk ducts and other connective tissue, the resulting DCIS tumours broke into the walls of the ducts.
"These findings made it clear that fibroblasts promote tumour growth and invasion, and normal myoepithelial cells suppress it," Polyak said.
However, when certain genes in the myoepithelial layer become under- or overactive, the layer breaks down and disappears, enabling tumour cells to escape.
In order to identify which genes are affected and what causes their activity level to change, researchers surveyed the activity of thousands of genes in myoepithelial and DCIS cells using advanced SAGE (Serial analysis of gene expression) technology.
When DCIS tumours trespass into the lining of the ducts, the activity level of several myoepthelial cell genes is abnormal -- specifically the TGF Beta, Hedgehog, and p63 genes as well as genes that help myoepithelial cells stick to 'basement' cells on the ducts' outer layer.
The effect is a cacaphony of erratic signals and haywire activity that prevents myoepithelial cells from fully maturing and forming an effective barrier to DCIS.
"We found a constant, complex interplay of signals among these genes, both within myoepithelial cells themselves, and between myoepithelial cells and their neighbours," Polyak said.
"The presence of DCIS causes the pattern of signals to change significantly, upsetting the normal development of myoepithelial cells. The myoepithelial cells fail to fully differentiate" -- act as true 'gatekeepers' for DCIS -- "leading to the disappearance of the myoepithelial layer and the beginning of tumour invasion," Polyak added.
According to Polyak, the discovery suggests that by scanning myoepithelial tissue for abnormalities in these key genes, doctors might be able to identify which women with DCIS have the greatest risk of cancer spread.
It also provides numerous targets for future drugs aimed at restoring the normal balance of signals among these genes.
"Our results highlight the importance of the microenvironment in breast tumour progression. And they suggest that therapies that target the interactions of tumour cells with their surroundings may offer a better way of inhibiting tumour progression than those that focus on the tumour epithelial cells alone," Polyak said.
The study is published in the May 6 issue of Cancer Cell.