| Lung cancer
is the leading cause of cancer deaths in the United
States. Bronchioalveolar carcinoma (BAC) is a
type of lung cancer that is more likely to strike
patients who are young, female and non-smokers.
As seen in other cancers, BAC is characterized
by the overactivity of multiple growth factor
signaling cascades. Growth factors interact with
receptors on or in the cell, changing the activity
of several cellular proteins that then affect
cellular structure and physiology. Several of
these factors depend on the structure of the extracellular
matrix (ECM), a complex mixture of proteins and
glycoproteins that surround cells. Far from just
holding cells together, the ECM modifies the activity
of a number of growth factor signaling cascades.
One modification mechanism depends on the sulfation
state of ECM proteins. The sulfation state is,
in turn, dependent on the expression of a protein
called HSulf-1. HSulf-1 removes specific sulfates
from the ECM, thereby reducing the signaling of
several growth factor cascades. Loss of HSulf-1,
on the other hand, promotes growth factor signaling
leading to tumor growth, invasion and resistance
to chemotherapy. The epidermal growth factor (EGF)
signaling cascade is frequently overactive in
BAC. Therapy with the new tyrosine kinase inhibitor
(TKI) drugs erlotinib and gefitinib, which target
the EGF pathway, has proven dramatically successful
in some patients with BAC. Specific mutations
within the EGF receptor are usually found in patients
that respond to TKI’s, although the correlation
is not 100%. The role of HSulf-1 in BAC is not
known although two of two BAC cell lines have
lost HSulf-1 expression. In addition to tumorigenesis,
loss of HSulf-1 has been correlated with invasion
in head and neck squamous cell carcinomas and
resistance to chemotherapy in ovarian and breast
carcinomas. The main objectives of this proposal
are to 1) Determine the mechanism of loss of HSulf-1
in 150 BACs, 2) Determine whether HSulf-1 expression
correlates with the clinical behavior of BACs
in these 150 tumors, with particular attention
to tumor spread, recurrence and response to TKIs
and finally, 3) Determine if HSulf-1 expression
is a predictive marker for TKI response. Understanding
the role of HSulf-1 in BAC biology will better
define potential mechanisms of drug resistance
and invasion in BAC and assess methods to overcome
them.
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