MISSION

is to identify and characterize key, novel tumor suppressor genes in breast cancer, and to study the utility
of these genes for diagnostic and therapeutic use. Tumor suppressor genes crucial for oncogenesis are often
targeted by multiple mechanisms of inactivation including mutation and promoter hypermethylation. Dr.
Chan and colleagues hypothesize that tumor suppressors that are key to the development of cancer can be
discovered by identifying common targets of multiple modes of inactivation. As such, the specific aims are
to 1) use combined global mutation and methylation analysis to identify common gene targets of mutation
and hypermethylation; 2) determine whether decreased expression of these “common target” genes predicts
for poor clinical prognosis in breast cancer and evaluate the use of these genes as biomarkers for outcome
in high risk breast cancer patients such as those with tobacco smoke exposure; and 3) determine the
function of the most promising candidate gene and evaluate this candidate as a tumor suppressor and
potential target of epigenetic therapy.
To this end, Dr. Chan and colleagues have developed a microarray approach that enables rapid and accurate
identification of genes silenced by hypermethylation in cancer. They used this technique to identify
genes silenced by hypermethylation in breast cancer. This dataset was then compared to the genes newly
discovered to be mutated in breast cancer (CAN genes). In all, 11 genes were found to be subject to both
mutation and cancer-specific methylation, and will be studied further. The relative roles played by mutation
versus methylation in disrupting gene function in cancer for these genes will be examined. Expression levels
of these 11 common target genes will be analyzed using well-annotated expression microarray datasets
from breast cancers to identify useful biomarkers for diagnosis and prognosis. As tobacco exposure is a
strong risk factor for poor outcome in patients with breast cancer, the use of these new genes as prognostic
biomarkers will be evaluated in breast cancer patients with this risk factor. This information may clarify the
use of adjuvant therapy for this group of high-risk breast cancer patients. Lastly, the molecular details of
the tumor suppressive function of the most promising and clinically significant gene (PTPRD) will be studied
using gene overexpression, RNA interference studies, and biochemical analysis. This study will allow
the discovery of novel cancer genes and explore the utility of these genes as useful predictors of clinical
prognosis and targets for therapy.
FAMRI Supported Publications
Chan TA, Glockner S, Mi Yi J, Chen W, Van Neste L, Cope L, Herman JG, Schuebel KE, Ahuja N, Baylin
SB. Convergence of mutation and epigenetic alterations identified common genes in cancer that predict
for poor prognosis. PLoS Med 2008;5(5):823-838.
Wong J, Armour E, Kazandies P, Iordachita I, Tryggestad E, Deng H, Matinfar M, Kennedy C, Liu Z,
Chan T, Gray O, Verhaegen F, McNutt T, Ford E, DeWeese TL. High-resolution, small animal
radiation research platform with x- ray tomographic guidance capabilities. Int J Radiat Oncol Biol Phys
2008;71:1591-1599.
CANCER, BREAST
COMPLETED RESEARCH
THE ROLE OF LYSINE HISTONE METHYLTRANSFERASE SET 7/9 IN BREAST CANCER
Nickolai A. Barlev, PhD; Tufts-New England Medical Center Hospitals; CIA 2005
Dr. Barlev and collaborators discovered a novel mechanism of p53 regulation, through lysine
methylation, by which p53 is upregulated in response to DNA damage. They investigated the molecular
mechanisms of p53 activation by lysine methylation in response to SHS, using a mammary cell model
system. In addition, they found that lysine methylation is not only required for activation of p53, but is
also necessary for global DNA repair. Elucidation of new downstream targets or effectors of this process
are important.
FAMRI Supported Publications
Morgunkova A., and Barlev, N.A. Lysine methylation goes global. Cell Cycle 5:pp. 1308-12; (2006)
Ivanov, G., Ivanova T., Kurash J.K.A, Ivanov, S., Gizzatullin F., Chuikov, F., Rauscher, D., Reinberg, and
Barlev, N.A. DNA damage activates p53 through a methylation-acetylation cascade. Mol Cell Biol (2008)
AN MVA VACCINE TARGETING p53 IN BREAST CANCER
Joshua Ellenhorn, MD; City of Hope; CIA 2005
The prupose of this project was to develop a vaccine against p53 antigen using an attenuated poxvirus,
modified vaccine Ankara (MVA) as a carrier vehicle to express p53 (MVAp53). The animal model used is a
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