| The ~ two-fold
higher risk of lung adenocarcinoma in women than
in men strongly suggests the involvement of gender-dependent
factors in the etiology of lung cancer (2). The
overall goal of the proposed research is to determine
the mechanism for this gender bias in lung adenocarcinoma.
The central focus is to identify differences in
the estradiol (E2)-induced proteome of lung adenocarcinoma
cells from female and male origin using cutting
edge bioanalytical and bioinformatic tools. We
recently reported that human lung adenocarcinoma
cell lines from females respond proliferatively
to E2 and were inhibited by the estrogen receptor
(ER) antagonists 4-hydroxytamoxifen (4-OHT) or
ICI 182,780 (1). In contrast, lung adenocarcinoma
cells from males were neither stimulated by E2
nor blocked by 4-OHT or ICI. Similar responses
were detected in transient transfections of these
cells with an estrogen response element (ERE)
reporter. Despite these differences, ER? and ER?
expression was similar among the cell lines from
males and females, indicating that lower ER expression
in cells from males is not responsible for the
observed phenotype. ER? expression was greater
than ER? in all lung cell lines. These results
suggest that lung adenocarcinoma cells from females
express proteins necessary for estrogenic responses
and that cells from males express reduced levels
of proteins necessary for ER activity. The proposed
experiments will test the hypothesis that E2 selectively
increases ER? interaction with proteins that stimulate
gene transcription resulting in cell replication
in lung adenocarcinoma cells from males but not
females. Functional proteomics will be used to
identify ER?- interacting proteins in representative
female versus male lung adenocarcinoma cell lines
upon E2 treatment by immunoprecipitation, SDS-PAGE,
and MALDI-TOF mass spectrometry. Bioinformatic
analysis of the results of this research will
help to define the molecular mechanisms of estrogen
action in lung adenocarcinoma. The second hypothesis
to be tested is that ER?-interacting proteins
that are differentially expressed in lung adenocarcinoma
cell lines from males and females will show the
same expression patterns in lung cancer tissue
samples from female and male lung cancer patients.
In the long term, our hope is that the results
of these studies will identify proteins that may
serve as biomarkers for the possible use of antiestrogens
or aromatase inhibitors or as therapeutic targets
to inhibit progression of lung adenocarcinoma
in both women and men.
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