NASA Scientific and Technical Aerospace Reports

effects of estrogen in bone, cardovasculature, and breast cancer. Cross talk could be caused by direct of indirect association
of these transcription factors, or by competition for other components of the transcriptional apparatus. In order to distinguish
among these possibilities, we identified clonal variants of ER(+) MCF-7 breast cancer cells that either do (MCF-7 SI) or do
not (MCF7 55) display ER mediated inhibition of NF-kappaB transcriptional activity. Transient transfection of various
coactivators intot he MCF- 7SS cells revealed that only CBP and p3OO were able to promote an inhibitory effect ofestradiolon
NF-kappa B activity. Western Bolt analysis showed that CEP protein levels were reduced in this cell line relate to the
MCF-7S1 cells. Both iminunofluorescent microscopy and co-immunoprecipitation shoed an associated between ER and
NF-kappaB in the MCF-7ST cells. CBP also immunoprecipitated with both ER and NF-kappaB. The use of deletion constructs
demonstrated that the ER ligand binding domain was necessary and sufficient for. ..
DTIC
Cancer; Estrogens; Mammary Glands; Receptors (Physiology)
20040111582 Texas Univ., Houston, TX
Arachidonate 15-Lipoxygenase 2 as an Endogenous Inhibitor of Prostate Cancer Development
Tang, Dean G.; Mar. 2004; 16 pp.; In English; Original contains color illustrations
Contract(s)/Grant(s): DAMD17-03-1-0137
Report No.(s): AD-A425644; No Copyright; Avail: CASI; A03, Hardcopy
Studies from our lab and others’ have implicated one class of lipid molecules, arachidonic acid (AA) lipoxygenases
(LOXs) and their products, in prostate tumorigenesis. Our recent work has demonstrated that: 1) 15- L%OX2, which
metabolizes AA to generate 15(S)-HErE, is the major LOX expressed in adult prOstate epithelial cells but down-regulated or
lo Pca in vitro as well as in’ vivo; 2)% 15- LOX2 expression is inversely correlated wfth%tii%%patholog%al grade and
Gleason score of PCa pThinenfs; 3) 15-LOX2 is a negative cell-cycle regulator in normal human prostate (NHP) epithelial
cells; 4) 15(S)-HErE inhibits PCa cell migration and invasion; 5) Re-expression of 15-LOX2, or its splice variant
iS-LOX2sv-b, inhibits PCa cell proliferation in vitro and tumor development in vivo. These observations suggest that
15-LOX2 may represent a fi%nctional prostate tumor suppressor, whose loss of expression contributes to PCa development.
We proposed two Specific Aims: 1) to test the hypothesis that 15- LOX2 inhibits PCa development in an onhotopic
implantation model using an inducible 15-LOX2 expression system; and 2) to test the hypothesis that 15-LOX2 inhibits PCa
development in newly developed prostate-specific transgenic animal models. By now we have finished most experiments in
Specific Aim 1, with a manuscript published in JBC. We are currently focusing on Specific Aim 2.
DTIC
Cancer; Inhibitors; Neoplasms; Prostate Gland
20040111583 Colorado Univ., Denver, CO
The Role of p90rsk in Breast Cancer Cell Survival from Apoptosis
Ghoda, Lucy Y.; Sep. 2003; 14 pp.; In English; Original contains color illustrations
Contract(s)/Grant(s): DAMD17-00-1-0475
Report No.(s): AD-A425646; No Copyright; Avail: CASI; A03, Hardcopy
Evidence suggests that sensitivity to chemotherapy is largely due to a functional apoptotic pathway. Thus, a better
understanding of the signal transduction pathways that lead to rescue from apoptosis might lead to improved modalities of
treatment for unresponsive cancer types. The focus of this proposal was to elucidate the role of p9Orsk in antagonizing
apoptosis in breast cancer cells. P9Orsk is a serine-threonine protein kinase in the Ras-Raf-ERK (extracellular signal-regulated
kinase, also known as mitogen- activated protein kinase or MAP kinase) cascade that lies immediately downstream of ERK.
Although the Ras pathway and ERKs have been the focus of much research in the cancer field, less is known about the role
of p9Orsk. We hypothesize that p9Orsk may be particularly relevant to breast cancer cell survival because evidence suggests
it can not only directly phosphorylate and activate the estrogen receptor but also has the potential to antagonize apoptosis
through neutralizing BAD, a proapoptotic member of he Bcl family of proteins. In addition, new evidence suggests to its
activation by PDKl (3- phosphatidyl inositol 3, 4, 5 phosphate dependent protein kinase) in addition to ERKl/2 activation. We
proposed to study p9Orsk since it may provide a new target in breast cancer therapy.
DTIC
Apoptosis; Cancer; Mammary Glands; Survival
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