Eppley Institute
Associate Director - Basic Research - UNMC Eppley Cancer Center
Associate Director, Eppley Institute ,
Identification and exploitation of new molecular targets in cancer
Research Interests
The Brattain Laboratory is
focused on the identification and exploitation of novel molecular
targets in cancer. There are two major areas of investigation that are
ongoing in the laboratory. One involves a group of molecules called
receptor tyrosine kinases (RTK’s) and signal transduction while the
other deals with control of gene expression in cancer by HDAC enzymes
that remodel chromatin and their inhibition of tumor suppressor activity
by TGFϐ
We are using shRNA approaches to stably knockdown novel RTK’s and
signaling targets to determine effects on tumor formation and growth in
vivo and to determine molecular mechanisms underlying these effects in
vitro. For example, we have developed orthotopic athymic mouse models of
human colon cancer that metastasize to the liver and lung similarly to
human disease. We have found that an RTK of the MET family, RON K, plays
an essential role in the metastatic process through inhibition of
orthotopic transplants of stable shRNA transfectants of colon cancer
cells bearing this receptor. Using similar approaches in vitro we have
now learned that this receptor activates a gain of function PI3 kinase
(PI3K) mutant that is essential to aberrant cell survival signaling
during the metastatic process. We are now pursuing the function of a
signaling intermediate of a recently identified link in the PI3K/AKT
pathway designated ARK.
We have had a long standing interest in the mechanisms which lead to
epigenetic repression of the TGFϐ type I and type II receptors in cancer
as both of these are required for the signaling of this tumor suppressor
and are frequently lost in a variety of cancers. Not surprisingly, the
Sp1 family is an important determinant of transcription in these TATA-
less genes. Using siRNA approaches and ChIP techniques we found that
both receptor genes are silenced by recruitment of HDAC1 to an Sp1/p300
complex. HDAC1 knockdown by siRNA results in re-expression of the
receptors with re-establishment of TGFϐ tumor suppressor activity. One
of the outcomes of TGFϐ tumor suppressor activity is the induction of
apoptosis. We have found that the mechanism by which this apoptosis is
driven is through the transcriptional repression of transcription of the IAP protein family member survivin. We are currently determining the
transcriptional mechanism associated with repression of survivin.
Tel: (402) 559-4902 (Office)
E-mail: Michael Brattain