| Lung cancer
is the leading cause of cancer deaths for men
and women. The higher frequency of lung adenocarcinoma
in women than in men, in both smokers and non-smokers,
suggests the involvement of gender-dependent factors
in lung cancer etiology. The long term goal of
the proposed research is to determine the mechanism(s)
responsible for this gender bias for lung adenocarcinoma
in women.
This proposal focuses on two topics: splice variants
of the mucin MUC1 as biomarkers for lung adenocarcinoma;
and interactions between MUC1 and estrogen receptors
that may affect susceptibility of men and women
to lung adenocarcinoma.
This proposal is based on three findings from
2006: [1] MUC1 binds to, stabilizes, and increases
the transcriptional activity of estrogen receptor
alpha (ER?) (1); [2] our collaborators reported
that although adenocarcinoma cells from both male
and female patients expressed ER?? and ER?, estradiol
stimulated proliferation only in cells from females
(2); and [3] our preliminary results indicate
an unexpectedly low frequency of the MUC1/A splice
variant in lung adenocarcinoma tumors and tumor
cell lines from male patients and a similarly
low frequency of the MUC1/B variant in tumor cells
from female patients. These data suggest that
MUC1/A and MUC1/B may represent biomarkers for
gender-specific susceptibility to lung adenocarcinoma.
Therefore, the goals of this project are to determine:
if the gender differences of MUC1/A and MUC1/B
frequencies can be used for risk assessment of
lung adenocarcinoma; and if interactions between
MUC1 and ER affect lung cancer susceptibility.
The hypothesis of this project is that these
gender-specific differences in susceptibility
to lung adenocarcinoma are related to interactions
between ER and MUC1 and reflect the genetics of
MUC1 splicing. Two specific aims will be investigated.
Aim 1 will characterize the MUC1/A and MUC1/B
splice pattern in lung adenocarcinoma. Additional
tumor samples will be analyzed to confirm that
the splice pattern differences are of statistical
significance. Five year survival data will be
used to determine if the splice variant pattern
correlates with survival. Also, we will determine
if the gender-specific splice variant difference
correlates with the status of an associated SNP
(rs4072037) and/or the size of the MUC1 tandem
repeat region. The results of this aim may establish
MUC1/A and MUC1/B splice variants as biomarkers
for susceptibility to lung adenocarcinoma. Aim
2 will characterize the interactions between estrogen
receptors and MUC1. We will determine if MUC1
interacts with both ER? and ER? in both male and
female lung adenocarcinoma cells and then determine
if there is a difference in the ability of the
MUC1/A and MUC1/B splice variants to interact
with ER.
The successful outcome of this project may lead
to the development of therapies based upon clinical
modulation of MUC1 expression.
References:
1. Wei XL, Xu H, Kufe D. MUC1 oncoprotein stabilizes
and activates estrogen receptor alpha. Molecular
Cell 2006; 21:295-305.
2. Dougherty SM, Mazhawidza W, Bohn AR, Robinson
KA, Mattingly KA, Blankenship KA, Huff MO, McGregor
WG, Klinge CM. Gender difference in the activity
but not expression of estrogen receptors alpha
and beta in human lung adenocarcinoma cells. Endocr
Relat Cancer 2006; 13:113-34.
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