| dc.description.abstract |
<p>Apoptotic dysregulation is a hallmark of cancer cells. The inability of cancer
cells to undergo apoptosis may lead to therapeutic resistance. Inflammatory breast
cancer (IBC) is a highly aggressive subtype of breast cancer that is often characterized
by ErbB2 overexpression and ErbB2 activation. ErbB-targeting is clinically relevant
using trastuzumab (anti-ErbB2 antibody) and lapatinib (small molecule ErbB1/2 inhibitor).
However, acquired resistance is a common outcome even in IBC patients who show an
initial clinical response, which limits the efficacy of these agents. Little is known
about the molecular mechanisms of therapeutic resistance in IBC cells. We hypothesized
that apoptotic dysregulation leads to therapeutic resistance of IBC cells to therapeutic
agents, including ErbB-targeting agents. To determine whether apoptotic dysregulation
and changes in anti-apoptotic proteins leads to resistance of IBC cells to therapeutic
agents, we performed a variety of in vitro-based studies using agents that are used
in the clinic to treat IBC patients. The sensitivity of both ErbB2 overexpressing
and ErbB1 activated IBC cells to various therapeutic agents was evaluated using various
cell death and apoptosis assays, and anti-apoptotic protein expression post-treatment
was determined using western blot analysis. The overarching theme observed was that
x-linked inhibitor of apoptosis protein (XIAP) expression inversely correlated with
sensitivity of cells to therapeutic agents with various mechanisms of action, including
TNF-related apoptosis inducing ligand (TRAIL), doxorubicin, cisplatin, paclitaxel,
and two ErbB-targeting agents: trastuzumab and a lapatinib-analog (GW583340). Moreover,
there was a specific and marked overexpression of XIAP in cells with de novo resistance
to trastuzumab and with acquired resistance to GW583340. The observed overexpression
was identified to be caused by IRES-mediated XIAP translation. Stable XIAP overexpression
using a lentiviral system reversed sensitivity to therapeutic agents (TRAIL and GW583340)
in parental IBC cells. Moreover, XIAP downregulation in cells resistant to therapeutic
agents (TRAIL, trastuzumab, and GW583340) resulted in decreased viability and increased
apoptosis, demonstrating that XIAP is required for survival of cells with resistance
to these agents. A novel mechanism of GW583340 oxidative stress-induced mediated
apoptosis was identified, and resistant cells had increased antioxidant expression
and capability. Interesting, inhibition of XIAP function overcame this increase in
antioxidant potential, demonstrating a new function for XIAP in oxidative stress-induced
apoptosis. These studies establish the feasibility of development of an XIAP inhibitor
that potentiates apoptosis for use in IBC patients with resistance to therapeutic
agents.</p>
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