NASA Scientific and Technical Aerospace Reports

the beta4 gene does not appear to be amplified in breast cancers that overexpress the alpha6beta4 integrin. We designed a probe
for beta4 mRNA useful in evaluating alpha6beta4 expression in formalin-fixed, paraffin-embedded tissues, and showed that
beta4 mRNA expression appears not to be a prognostic factor in node-negative invasive breast carcinoma. Adhesionindependent
cross-linking of alpha6beta4 was found to be associated with phosphorylation of nonmusole myosin II heavy
chain, which may affect actin-myosin filament organization. We showed by immunofluorescence microscopy that cell-surface
alpha6beta4 clustering can be demonstrated following antibody- mediated cross-linking of the integrin not only in cell lines
but also in fine-needle aspirates of breast carcinoma specimens. Although we could not demonstrate clinical significance in
this study, further refinements are needed in the techniques to induce and detect integrin clustering in carcinoma specimens
in order to determine whether detection of integrin clustering as a surrogate of integrin function will ultimately prove to be
useful clinically.
DTIC
Cancer; Mammary Glands; Markers
20040111647 Albany Medical Coll., NY
Identification of Cellular Binding Sites for a Novel Human Anti-Breast Cancer Peptide
DeFreest, Lori; Bennett, James; May 2004; 20 pp.; In English
Contract(s)/Grant(s): DAMD17-02-1-0269
Report No.(s): AD-A425751; No Copyright; Avail: CASI; A03, Hardcopy
We have synthesized a nine amino acid peptide, AFPep, that inhibits the growth of ER+ human breast. Understanding the
process by which AFPep mediates its inhibitory activity is extremely important for the development of this drug or other drugs
which exploit the same biochemical pathways to arrest breast cancer growth. We have developed and optimized an affinity
chromatography procedure to identify the receptor for AFPep by using the peptide as ‘bait’ to isolate proteins from solublized
cells which have an affinity for the peptide. A protein of approximately 70 kDa which shows specificity for the linear form
of the peptide, AFPep, has been isolated and identified by mass spectroscopy as Hsp72 which together with Hsp9O and other
components forms a heterocomplex that binds to the ER and mediates ligand binding and transcriptional activities. The
specificity of the interaction between AFPep and Hsp72 and the relevance to the anti-breast cancer activity of AFPep are
currently being evaluated. In addition, an in vitro cell culture method which shows consistent inhibition by AFPep of
estrogen-stimulated growth of human breast cancer cells has been developed and will be used to evaluate the mechanism of
action of the peptide.
DTIC
Cancer; Chemical Bonds; Mammary Glands; Peptides
20040111648 Queensland Inst. of Tech., Brisbane
A Novel Method to Screen for Dominant Negative ATM Mutations in Familial Breast Cancer
Khanna, Kum K.; Apr. 2004; 18 pp.; In English; Original contains color illustrations
Contract(s)/Grant(s): DAMD17-02-1-0556
Report No.(s): AD-A425752; No Copyright; Avail: CASI; A03, Hardcopy
The ATM gene is mutated in the autosomal recessive disorder, ataxia telangiectasia (A-T), which is characterised by
cancer predisposition, cerebellar ataxia and immunodeficiency. One of the most controversial topic in breast cancer genetics
is whether mutations in the A TM gene predispose women to breast cancer. Studies of A-T families appear to have an elevated
frequency of breast cancer in females, particularly in obligate heterozygotes whose risk may be increased as much as 7-fold.
By contrast, most studies of sporadic breast cancer have not found an increased frequency of germline A TM mutations
compared with controls, and linkage analysis of markers close to ATM in multiple-case families has provided no evidence that
the ATM gene predisposes women to breast cancer. Nevertheless, two recurrent A TM mutations, T7271G and IVS1-6T-\gG,
were recently reported to be associated with breast cancer (Stankovic et al., 1998; Broeks et al., 2000). We analysed these two
pathogenic mutation in ATM in female-breast cancer only, non-BRCA1/2 families in the Australian based Kathleen
Cunningham Foundation Consortium for Research into Familial Breast Cancer (KConFab) and observed that 3% of the
families carried one of the two mutations in ATM analysed (Chenevix-trench et al, 2002). We have shown that both mutations
act as dominant negatives in that ATM kinase activity was markedly reduced in the heterozygous carriers of these mutations.
These observations suggest that a proportion of hereditary breast cancer may be due to ATM mutations, and that the increased
breast cancer risk may be restricted to a subset of A TM mutations.
DTIC
Cancer; Mammary Glands; Mutations
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