| The fact that
women, even non-smokers, are at higher risk than
men for developing a type of lung cancer called
lung adenocarcinoma strongly suggests the involvement
of gender-dependent factors in the etiology of
lung adenocarcinoma. The overall goal of the proposed
research is to determine the mechanism for this
gender bias in lung adenocarcinoma. We recently
published a paper showing that lung adenocarcinoma
cell lines from female lung cancer patients were
stimulated to replicate by estrogen and that the
growth of these cells was blocked by the anti-estrogen
tamoxifen, commonly used to treat women with breast
cancer (1). In contrast, lung adenocarcinoma cells
from male patients did not respond to estrogen
or antiestrogens. These data suggest the possibility
that women with lung adenocarcinoma might benefit
from the use of antiestrogen therapy. In order
for cells to respond to estrogen, the cells must
express estrogen receptors. There are 2 types
of estrogen receptors (ER) called ER? and ER?.
Interestingly, although the lung adenocarcinoma
cell lines from males did not respond to estrogen
or ER antagonists, they expressed as much ER?
and ER? as did the estrogen-responsive lung adenocarcinoma
cells from females. This means that something
beyond ER is different between the lung adenocarcinoma
cells from women and men. Because ER? is the predominant
ER in lung adenocarcinoma cell lines, our goal
in the present study is to find out if the estrogen-responsive
cells from females make proteins that interact
with ER? that allows the cells to respond to estrogens
and antiestrogens and whether lung adenocarcinoma
cells from males do not express these ER?-interacting
proteins. In Aim 1 we will test the hypothesis
that E2 selectively increases ER? interaction
with proteins that upregulate gene transcription
and cell proliferation in lung adenocarcinoma
cells from females but not males. In Aim 2 we
will examine the expression of 2 of these proteins
identified in Aim 1 in clinical lung tumor specimen
from male and female patients and correlate protein
expression with other measures of disease including
survival. Results of these studies will tell us
what proteins are differentially expressed in
lung adenocarcinoma cells from women and men that
could be targets of therapy to inhibit the progression
of lung adenocarcinoma.
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