| dc.description.abstract |
<p>Tumor recurrence following initial treatment is the leading cause of death among
breast cancer patients. Epigenetic mechanisms are critical for regulation of gene
expression and to facilitate appropriate responses to environmental cues. However,
it is increasingly appreciated that epigenetic dysregulation directly promotes therapeutic
resistance and tumor progression. While genetic alterations have been shown to promote
tumor progression, the contribution of non-genetic drivers of recurrence remains unexplored.
In the current work, we utilized genetically engineered mouse models of breast cancer
recurrence to evaluate the contribution of epigenetic plasticity to tumor recurrence
and chemoresistance. First, we found that recurrent tumors undergo dramatic epigenetic
and transcriptional reprogramming, partially through acquisition of an epithelial-to-mesenchymal
transition (EMT). EMT promoted epigenetic silencing of tumor suppressor Par-4 through
a unique, bivalent histone configuration. This bivalent configuration conferred plasticity
to Par-4, and Par-4 silencing was reversed with epigenetic inhibitors of EHZ2 and
HDAC. Further, Par-4 re-expression sensitized recurrent tumors to commonly utilized
microtubule-targeting chemotherapeutics through altered cytoskeletal regulation. Second,
we found that recurrent tumor epigenetic and transcriptional rewiring conferred sensitivity
to G9a inhibitors. G9a inhibition promoted recurrent tumor cell necroptosis through
demethylation of genes involved in a pro-inflammatory cytokine program. Further, knockout
of G9a protein delayed the time until mammary tumors recurred in vivo. Collectively,
our studies demonstrate that epigenetic dysregulation is a key feature of breast cancer
progression, and pharmacologic strategies designed to target epigenetic enzymes underlying
these processes may be of clinical value in the treatment of recurrent breast cancer.</p>
|
|
