NASA Scientific and Technical Aerospace Reports

The objective of this proposal is to identify fingerprints or ‘keystone’ markers based on clinical outcome using tissue
microarrays (TMAs) and automated analysis (AQUA). This is a novel method that will allow the identification of ‘prognosis
fingerprints’ important in disease-specific breast cancer survival. While the original proposal focused on construction of only
lymph node-negative tissue microarrays, node-positive specimens have been included to help find markers that can separate
patients based on their nodal status and to assist in the discovery of biomarkers important in a ‘prognosis’ signature for breast
cancer regardless of nodal status. As of this progress report, we have completed the construction of the tissue microarrays, the
collection of the clinical data for the cohort, and the assessment of the tissue microarrays with standard clinical biomarker
antibodies (ER, PR, Her2 and Ki-67). We are currently in the process of analyzing over 40 biomarkers on the tissue
microarrays by AQUA for their prognostic value individually, and multiplexed with other biomarkers and clinicopathological
data, in order to determine which biomarkers are key in subclassifying the breast cancer tumor cohort.
DTIC
Cancer; Mammary Glands; Tissues (Biology)
20040111613 Fox Chase Cancer Center, Philadelphia, PA
The Nuclear Death Domain Protein p84N5; a Candidate Breast Cancer Susceptibility Gene
Godwin, Andrew K.; May 2004; 17 pp.; In English; Original contains color illustrations
Contract(s)/Grant(s): DAMD17-03-1-0312
Report No.(s): AD-A425704; No Copyright; Avail: CASI; A03, Hardcopy
Besides family history of cancer and an individual’s age, no single etiologic factor can identify women at an increased
risk for the disease. Approximately 10% of all cases of breast cancer exhibit a familial pattern of incidence. Efforts to identify
the genetic basis of familial breast cancer reached fruition some years ago, when the breast- cancer susceptibility genes,
BRCAl and BRCA2 were identified. However, recent studies have suggested that mutations in these genes are associated with
a smaller number (20 to 60%) of hereditary breast cancer families than originally estimated, especially in studies that have
been based on population- based family materials. Several groups including ours are searching for additional breast cancer
susceptibility genes using whole genome scanning approaches, but the success of many of these approaches depend on the
underlying heterogeneity of the remaining cancer susceptibility loci. The failure to date to identify additional breast cancer
susceptibility genes associated with a high risk of disease suggests that more than one may exist. We have taken the approach
that the next BRCA genes will be those that encode for proteins whose functions are linked to important cell regulatory
pathways. We have recently found one such candidate BRCA3 protein, referred to as p84N5.
DTIC
Cancer; Death; Genetics; Mammary Glands; Oncogenes; Proteins
20040111618 Georgetown Univ., Washington, DC
Strategies of Discovering Small Molecule Drugs Targeting Growth Factor Heregulin
Yang, Dajun; Jan. 2002; 19 pp.; In English
Report No.(s): AD-A425712; No Copyright; Avail: CASI; A03, Hardcopy
Heregulin (HRO) constitutes the HRG subfamily of EOF-related peptides that were isolated from breast cancer cell line
MDA-MB-23 1, and ras-transformed Rat-i fibroblasts. HRG can stimulate proliferation and may function as an autocrine
growth factor in transformed mammary epithelial cells. Stable expression of HRG via transfection leads tumor formation in
nude mice and might perform a role in progression to estrogen-independent tumor growth. Furthermore, HRG induces in vivo
lobuloalveolar development of mammary gland, and in MMTV-HRG transgenic mice, HRO induces mammary
adenocarcinoma, and hyperplasia. Clinically, elevated expression of HRO play a role in breast cancer growth and progression
and is associated with less favorable disease outcome. We have used a structure- based strategy towards the discovery of small
molecules as potential HRG antagonists. Small, non-peptidal molecules which mimics the 3D structure of HRG binding
domain could specifically block ligand receptor-binding. Lead compound SMA 1 demonstrated activity as specific antagonists
of HRO in receptor binding competition, HRG-induced phosphorylation as says and HRO-dependent cell proliferation assays.
Inhibition of HRO- induced phosphorylation or cell growth can be reversed by addition of extra amount of HRG, suggesting
the compound SMA 1 may function as HRG antagonist. The discovery of compounds represents an important step in the
development of the small molecule, HRO antagonists as potential clinical candidates in the prevention and treatment of breast
cancer.
DTIC
Cancer; Drugs; Exploration; Mammary Glands
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