Kornelia Polyak, MD, PhD
When a form of cancer that begins in the milk ducts of the breast
invades neighboring tissue to spread to other parts of the body, the
cause lies not in the tumor cells themselves but in a group of abnormal
surrounding cells that cause the walls of the duct to deteriorate like a
rusty pipe, according to a new study led by Dana-Farber Cancer
The discovery, reported in the May 6 issue of Cancer Cell,
may 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
it 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,"
according to 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 tumor's microenvironment — the cells and tissue that
surround the cancer."
DCIS is expected to be diagnosed in nearly 53,000 women in the United
States this year. When detected and surgically removed before it has a
chance to spread, the disease is nearly always curable. It isn't known
how many of these cancers would become invasive breast cancer if they
weren't treated, but studies suggest that most of them eventually would.
Researchers initially thought that DCIS might become invasive as a
result of genetic changes in the cancer cells. When they surveyed gene
activity in immobile DCIS cells and in those that had spread, however,
they found no significant differences. That led them to consider the
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. To study what role, if any, these cells play in DCIS, the
researchers worked with a specially engineered line of cells known as
When injected in laboratory animals, the MCFDCIS cells formed
DCIS-like tissue that developed into invasive tumors, providing a good
model of what happens in human disease. When researchers injected both
MCFDCIS and myoepithelial cells into the mice, DCIS tumors 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 tumors broke into the walls of the ducts.
"These findings made it clear that fibroblasts promote tumor growth
and invasion, and normal myoepithelial cells suppress it," Polyak
remarks. But when certain genes in the myoepithelial layer become under-
or overactive, the layer breaks down and disappears, enabling tumor
cells to escape.
To identify which genes are affected and what causes their activity
level to change, Polyak's team surveyed the activity of thousands of
genes in myoepithelial and DCIS cells using advanced SAGE (Serial
analysis of gene expression) technology. When DCIS tumors 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 neighbors," Polyak says. "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 tumor
The discovery suggests that by scanning myoepithelial tissue for
abnormalities in these key genes, doctors may be able to identify which
women with DCIS have the greatest risk of cancer spread, says Polyak,
who is also an associate professor of medicine at Harvard Medical
School. 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 tumor progression," Polyak remarks. "And they suggest that
therapies that target the interactions of tumor cells with their
surroundings may offer a better way of inhibiting tumor progression than
those that focus on the tumor epithelial cells alone."
The study's lead author is Min Hu, PhD, of Dana-Farber. Co-authors
are Jun Yao, PhD, Haiyan Chen, PhD, Erica Bauerlein, Daniel Carrasco,
MD, PhD, William Hahn, MD, PhD, and Rebecca Gelman, PhD, of Dana-Farber;
Stanislawa Weremowicz, PhD, and Andrea Richardson, MD, PhD, of Brigham
and Women's Hospital; Danielle Carroll, PhD, of Harvard Medical School;
Sheila Violette, PhD, of Biogen-Idec of Cambridge, Mass.; Tatiana
Nikolskaya, PhD, and Yuri Nikolsky, PhD, of GeneGo, Inc., of St. Joseph,
Mich.; Craig Allred, MD, of Washington University School of Medicine;
Mina Bissell, PhD, of Lawrence Berkeley National Laboratory; and Stuart
Schnitt, MD, of Beth Israel Deaconess Medical Center.
Funding for the study was provided by the National Institutes of Health, the Susan G. Komen Foundation, and Biogen-Idec.
Dana-Farber Cancer Institute (www.dana-farber.org)
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United States.
It is a founding member of the Dana-Farber/Harvard Cancer Center
(DF/HCC), designated a comprehensive cancer center by the National