NASA Scientific and Technical Aerospace Reports

20040111654 California Univ., Los Angeles, CA
Angiogenesis Inhibitors in Breast Cancer
Luque, Alfonso; Iruela-Arispe, Luisa; Apr. 2004; 10 pp.; In English
Contract(s)/Grant(s): DAMD17-02-1-0329
Report No.(s): AD-A425759; No Copyright; Avail: CASI; A02, Hardcopy
ADAMTSl/METHl is a secreted protease that belongs to the metallospondin/ ADAMTS sub-family of the zincmetalloprotease
superfamily. This family is characterized by proteins that contain a modular structure that includes A,
Disintegrin-like, Metalloprotease, and type-1 ThromboSpondin domains. ADAMTSl has been shown to inhibit both
endothelial cell proliferation in vitro, as well as angiogenesis in vivo. We have investigated the role of ADAMTSl and its
proteolytic activity, through the creation of a catalytically inactive mutant (ADAMTSl(sub E385A), in tumor growth by
overexpressing the coding region in a human breast carcinoma cell line (T47D) and generating xenograft tumors in nude mice.
T47D ADAMTSl(sub E385A) tumors displayed no significant difference in growth kinetics when compared to CON tumors;
whereas wild-type ADAMTSl tumors exhibited two-fold growth inhibition at 40 days post- implantation. We have also studied
the activity of ADAMTSl on endothelial cells in vitro and have determined that ADAMTSl releases proteins from the cell
surface. We also provide evidence to support that the catalytic activity of ADAMTSl either directly or indirectly affects growth
factor signaling impairing VEGF:VEGFR2 interactions both in vitro and in vivo. Thus ADAMTSl can be distinguished as a
secreted metalloprotease that inhibits tumor growth and angiogenesis through its activity as a protease.
DTIC
Cancer; Inhibitors; Mammary Glands
20040111655 Georgetown Univ., Washington, DC
EGF Regulation of Nuclear Co-Activator AIB1 Function in Breast Cancer
Oh, Annabell; Riegel, Anna; Apr. 2004; 12 pp.; In English
Contract(s)/Grant(s): DAMD17-02-1-0394
Report No.(s): AD-A425761; No Copyright; Avail: CASI; A03, Hardcopy
Various growth factor receptor pathways promote human breast tumorigenesis of hormone independent tumors. The
nuclear receptor coactivator AIBl (amplified in breast cancer 1) can be phosphorylated and regulated by growth factor- induced
signaling pathways such as MAP kinase and IkB kinase. Our lab has found a splice variant of AIBl, called delta exon3 AIBl,
which has a higher co-activating ability than the full- length protein. This study determined the ability of delta exon3 splice
variant compared with AIBl in potentiating growth factor signaling and to determine the mechanism of this potentiation using
a growth factor responsive promoter.
DTIC
Activation; Cancer; Hormones; Mammary Glands; Nuclear Medicine; Receptors (Physiology)
20040111656 Michigan Univ., Ann Arbor, MI
Genetic Determinants of Inflammatory Breast Cancer
Merajver, Sofia D.; Jul. 2003; 11 pp.; In English
Contract(s)/Grant(s): DAMD17-00-1-0345
Report No.(s): AD-A425765; No Copyright; Avail: CASI; A03, Hardcopy
Primary inflammatory breast cancer (IBC) accounts for approximately 6% of new breast cancers annually. We
hypothesized that a limited number of concordant genetic alterations give rise to the unioue aggressive inflammatory
phenotype of IBC. While working on the genetic determinants underlying the IBC phenotype, we found concordant and
consistent alterations of two genes, RhoC GTPase and a novel IGF-binding protein (IGF-BP), in patients with IBC. RhoC was
overexpressed in 90% of IBC samples examined compared to 30% of stage matched non-IBO tumors. LIBC was lost in 80%
of the IBC samples and only 20% of non-IBC samples examined. Since RhoC and LIBC appear to act in concert in IBC,
coupled to the preliminary evidence from other laboratories of genes from these families playing a role in pancreatic cancer
(another highly aggressive adenocarcinoma), they are excellent candidate genes to begin to probe the genetic basis of the
aggressive phenotype in IBC. We hypothesize that the phenotype of IBC is due to alterations in expression of RhoC and
IGF-BP early in tumorigenesis. We will elucidate the signaling pathway downstream from RhoC CTPase and attempt to
determine what effect RhoC and LIBC have on cellular motility and invasion.
DTIC
Cancer; Genetics; Mammary Glands
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