NASA Scientific and Technical Aerospace Reports
NASA Scientific and Technical Aerospace Reports
NASA Scientific and Technical Aerospace Reports
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20040073582 Scripps Research Inst., La Jolla, CA<br />
Blocking Blood Supply to Breast Carcinoma with a DNA Vaccine Encoding VEGF Receptor-2<br />
Xiang, Rong; Apr. 2004; 30 pp.; In English; Original contains color illustrations<br />
Contract(s)/Grant(s): DAMD17-02-1-0562<br />
Report No.(s): AD-A422420; No Copyright; Avail: CASI; A03, Hardcopy<br />
The major goal of cancer immunology is to induce a tumor protective immune response that could effectively eradicate<br />
growth <strong>and</strong> dissemination of metastases. In our second fiscal year, we demonstrated proof of concept indicating that effective<br />
suppression of tumor angiogenesis can be achieved with a DNA vaccine encoding either muring VEGF receptor-2 (Flk-1) or<br />
Flk-1 minigenes designed to induce CTL- mediated immune responses by targeting proliferation endothelial cells in the tumor<br />
vasculature. In fact, CTL- medicated killing of endothelial cells indicated a breaking of peripheral immune tolerance against<br />
FLK-1 or fragments of this self-antigen resulting in markedly reduced dissemination of metastases. Angiogenesis in the<br />
vasculature was suppressed without impairment of fertility, neuromuscular performance or hematopoiesis <strong>and</strong> with only a<br />
slight delay in wound healing. Furthermore, a similar strategy was performed by targeting the transcription factor Fra-1<br />
co-expressing secretory IL-18, in breast cancer model, which was highly effective in suppression or eradicating aggressive<br />
metastases by inducing anti- angiogenesis coupled with pronounced activation of T <strong>and</strong> NK cells. We demonstrated that this<br />
combination could not only suppress D2F2 breast cancer growth <strong>and</strong> metastases, but also induces a long-lived T cell memory.<br />
DTIC<br />
Blocking; Blood Volume; Cancer; Coding; Deoxyribonucleic Acid; Mammary Gl<strong>and</strong>s; Vaccines<br />
20040073584 Cincinnati Univ., OH<br />
Conditional Estrogen Receptor Knockout Mouse Model for Studying Mammary Tumorigenesis<br />
Khan, Sohaib A.; Jan. 2004; 13 pp.; In English<br />
Contract(s)/Grant(s): DAMD17-00-1-0057<br />
Report No.(s): AD-A422422; No Copyright; Avail: CASI; A03, Hardcopy<br />
In addition to accomplish the main goal of this grant proposal, i.e. to generating mice with estrogen receptor (ER) alpha<br />
gene ablation in the mammary gl<strong>and</strong> of mice, we have also carried out other tasks. A summary of our findings follows: (1)<br />
In order to identify targets of ER-alpha, ER-beta genes, we used microarray <strong>and</strong> profiled the targets for estrogen <strong>and</strong> bis<br />
phenol-A. This will be of help in underst<strong>and</strong>ing the mechanism by which different lig<strong>and</strong>s function in the breast cancer cells.<br />
(2) We identified the F- domain of ER-alpha as playing an important role in the regulation of ER activity. (3) We constructed<br />
ER-alpha targeting vectors <strong>and</strong> generated ER-alpha embryonic cell lines. (4) We generated floxed ER-alpha mice, which will<br />
be used to generate tissue specific mice (e.g. mammary). Thus these tools <strong>and</strong> results will be of great use in underst<strong>and</strong>ing<br />
breast cancer disease process with reference to the role of estrogen receptor.<br />
DTIC<br />
Cancer; Estrogens; Knockout Mice; Mammary Gl<strong>and</strong>s<br />
20040073585 California Univ., San Diego, La Jolla, CA<br />
The Contribution of Hypoxia-Inducible Factor (HIF) -1 Alpha to Normal Mammary Gl<strong>and</strong> Development <strong>and</strong><br />
Mammary Tumorigenesis<br />
Seagroves, Tiffany N.; Oct. 2003; 41 pp.; In English; Original contains color illustrations<br />
Contract(s)/Grant(s): DAMD17-01-1-0186<br />
Report No.(s): AD-A422423; No Copyright; Avail: CASI; A03, Hardcopy<br />
During pregnancy the mammary epithelium <strong>and</strong> its supporting vasculature rapidly exp<strong>and</strong> to prepare for lactation. To<br />
investigate the role of oxygenation <strong>and</strong> metabolism in these processes the oxygen-responsive component of the hypoxiainducible<br />
factor (HIF)-1 complex, HIF-1 alpha, was deleted in the murine mammary gl<strong>and</strong> using the Cre/loxP system.<br />
Although vascular density remained similar, loss of HIF-1 alpha impaired mammary differentiation <strong>and</strong> lipid metabolism,<br />
culminating in lactation failure <strong>and</strong> changes in milk composition (Objectives #1) . Next, we investigated the effects of deletion<br />
of the von Hipple Lindau (VHL) gene in the mammary gl<strong>and</strong>, in order to stimulate constitutive over- expression of HIF-1<br />
alpha the mammary epithelium, to determine if HIF-1 alpha contributes to mammary gl<strong>and</strong> tumorigenesis (Revised Objective<br />
#2) . Preliminary results from this work indicate that VHL is also an important mediator of normal mammary gl<strong>and</strong><br />
differentiation, confirming that regulation of the hypoxic response is critical for normal mammary gl<strong>and</strong> development. The<br />
ultimate goal is of these experiments is to determine the role of HIF-1 alpha over-expression during mammary gl<strong>and</strong><br />
tumorigenesis.<br />
DTIC<br />
Cancer; Hypoxia; Mammary Gl<strong>and</strong>s<br />
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