May 08, 2009
Novel gene predicts local recurrence in early onset breast cancer
A newly discovered gene known as DEAR1 is mutated in breast cancer
and is an independent predictor of local recurrence-free survival in
early-onset breast cancer, a research team headed by scientists at The
University of Texas M. D. Anderson Cancer Center reports in the journal
PLoS Medicine.
"The correlation with local recurrence
is significant because so many young women have recurrences in the
breast, and cancers that do recur tend to be more aggressive," said
senior author Ann McNeill Killary, Ph.D., professor in M. D. Anderson's
Department of Genetics. "Young age has been considered a risk factor
for local recurrence and metastasis. It is important to understand the
genetic mechanisms operating in early-onset breast cancer and to
determine whether there is a way to identify young women who might be
at a higher risk of recurrence."
After Killary's laboratory
research discovered DEAR1 (ductal epithelium-associated ring chromosome
1) and implicated it in breast cancer, the team examined a tumor tissue
microarray from 123 women whose breast cancer began between ages 25 and
49, all of whom advanced to invasive disease. Of these, 56 percent
lacked DEAR1 expression in their tumors, which was associated with 58
percent local recurrence-free survival 15 years after surgery. For
those with DEAR1 expression, local recurrence-free survival was 95
percent at 15 years.
"Immunohistochemical staining for DEAR1
could potentially be performed in any hospital setting, and such an
assay might predict which women are at a high risk of recurrence and
potentially help guide treatment decisions" Killary said, noting the
results will need to be validated in a larger cohort of patients.
Breast
cancer that develops before age 50 tends to be more aggressive and more
likely to recur even in the absence of invasion of the lymph nodes at
diagnosis. "Approximately one-fourth of women without nodal involvement
will experience a recurrence up to 12 years after surgery," Killary
said. Of the 123 early-onset patients, 72 percent had no lymph node
involvement at diagnosis.
Low expression associated with triple-negative breast cancer
While
the researchers found that loss of DEAR1 expression correlated
significantly with local recurrence, it did not correlate with overall
survival in this young cohort.
However, lack of DEAR1
expression was associated with triple-negative breast cancer, which
indicates poor prognosis because it lacks estrogen or progesterone
receptors and does not express HER2, three targets for therapy. Lack of
DEAR1 expression also was associated with a strong family history of
breast cancer.
The team discovered the gene in a region of the
human genome that has been implicated in other epithelial tumors,
including colon and pancreatic cancers, and that the researchers
suspected might harbor an important tumor suppressor gene. Finding that
DEAR1 was mutated in breast cancer suggested that it could play a role
in the initiation and progression of the disease.
The
researchers found evidence that DEAR1 plays a critical regulatory role
in acinar morphogenesis, or the orderly development and differentiation
of the terminal ductal lobular units (TDLU) in the breast. TDLUs are
structures present at the ends of a branching network of ducts in the
normal mammary gland which also are thought to be the site of origin of
many breast cancers. Mutations in DEAR1 lead to cellular
disorganization, lack of cell differentiation, and loss of normal
structure in breast tissue - all hallmarks of a transition to
malignancy.
Mutated or deleted DEAR1 causes structural dysfunction
The
researchers tested their theories in an experimental model using
three-dimensional basement membrane culture systems designed to
reproduce the tissue architecture of the mammary gland.
The
first experiment tested whether placing a normal DEAR1 gene into a
cancer cell could re-establish a more normally functioning cell.
Killary noted that when tumor cell lines containing a DEAR1 mutation
were grown in the culture system, the cells showed aberrant growth and
formed large clumps of cells with no organized structure. Inserting a
normal DEAR1 gene restored acinar morphogenesis and resulted in
structures that were very similar to those present in normal breast
tissue.
In a second tissue culture experiment, the
researchers shut down expression of the DEAR1 gene in normal breast
epithelial cells, which caused the cells to lose their ability to form
proper structures.
In addition, the researchers used
immunohistochemical staining to examine DEAR1 expression in 14 samples
of ductal carcinoma in situ (precancerous abnormalities) with adjacent
normal epithelium and in the corresponding invasive cancer from the
same patient. They found that DEAR1 was expressed in all the normal
ducts in the glands but was lost or downregulated in the transition
from normal epithelium to DCIS in 10 of the 14 patient samples.
This
research was funded by the Texas Advanced Research Program, The U. S.
Department of Defense, the National Cancer Institute Early Detection
Research Network, National Cancer Institute training grant, the
National Kidney Foundation, and by the Ladies Auxiliary to the Veterans
of Foreign Wars.
Co-authors with Killary are Steven T. Lott,
Ph.D., Nanyue Chen, M.D., Ph.D., Dawn S. Chandler, Ph.D., Luo Wang,
Ph.D., Marivonne Rodriguez, Hongyan Xie, Ph.D., Seetharaman
Balasenthil, Ph.D., Katrina Chaung, Baili Zhang, Ph.D., Shodimu-Emmanu
Olufemi, Ph.D., Henry Adams, and Ralf Krahe, Ph.D., all of M. D.
Anderson's Department of Genetics; Qifeng Yang Ph.D., and Bruce Haffty,
M.D., of the University of Medicine and Dentistry of New Jersey-Robert
Wood Johnson Medical School's Department of Radiation Oncology; Thomas
A. Buchholz, M.D., of M. D. Anderson's Department of Radiation
Oncology; Aysegul A. Sahin, M.D., Adel K. El-Naggar, M.D., Ph.D., and
Subrata Sen, Ph.D., of M. D. Anderson's Division of Pathology and
Laboratory Medicine; Jinyue Chen, Ph.D., and Marsha Frazier, Ph.D., of
M. D. Anderson's Department of Epidemiology; Vimla Band, Ph.D., of the
University of Nebraska Medical Center, Eppley Cancer Center's
Department of Genetics, Cell Biology, and Anatomy; Khandan Keyomarsi,
Ph.D., of M. D. Anderson's Department of Experimental Radiation
Oncology; Kelly K. Hunt, M.D., of M. D. Anderson's Department of
Surgical Oncology; and Stephen M. Hewitt, M.D., Ph.D., of the National
Cancer Institute's Tissue Array Research Program in the Laboratory of
Pathology and Center for Cancer Research.
Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
SOURCE:
University of Texas M. D. Anderson Cancer Center
