| SWI/SNF is
an important chromatin remodeling complex that
serves a pivotal role in the regulation and control
of gene expression. Transcription factors and
key cellular proteins recruit this complex to
a specific DNA domain where it either promotes
and/or blocks gene expression by shifting the
position of histone within the chromatin. The
SWI/SNF complex was first definitively linked
to tumorigenesis when it was found that its subunit,
BAF47, is a bona fide tumor suppressor protein
and the key event in the development of rhabdoid
sarcoma, a lethal pediatric tumor. We have found
that the ATPase subunits BRG1 and BRM, which are
essential for complex function, are concomitantly
lost in 30-40% of lung cancer cell lines and 10-20%
of primary lung cancers as well as other solid
tumors. Our mouse studies have shown that the
loss of either protein leads to increased cancer
susceptibility by interfering with local growth
control mechanism, such as retinoic acid receptors
(RAR). These receptors are known to both inhibit
proliferation and impede the development of tumors
in in vivo animal models. Since they are functionally
dependent on the SWI/SNF complex, they will inevitably
be negatively impacted when either BRM or BRG1
are lost during tumor development. Thus, we hypothesize
that alterations to the SWI/SNF complex not only
occur in NSCL cancer but also likely underlie
and contribute to the develop of BACs. Mechanistically,
this will promote cancer development by inactivating
regulatory pathways dependent on the SWI/SNF complex,
including RAR. To understand the potential role
of the SWI/SNF complex in the genesis of BAC,
we have proposed to immunostain our BAC tissue
microarray consisting of 150 pathological verified
cases and determine if BRG1, BRM or other SWI/SNF
subunits are lost. Additionally, we have proposed
to discover the mechanism of their abrogation
by sequencing these genes. To clarify how these
potential changes strip the cell of its growth
control mechanism, thereby allowing the development
of BAC, we specifically focus on examining the
effects of BRM loss on the antitumorigenic effects
of retinoids using an established animal model.
These studies are not only important because they
provide much need tools for the study of BAC,
but also because they help define novel molecular
change, which could assist the development of
relevant clinically targeted therapies. Finally,
these studies have the potential to explain why
retinoids have not been found to have chemopreventive
effects in lung cancer.
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