Triple-negative breast cancer (TNBC) remains a deadly disease despite recent new treatments. Therefore,
additional treatment strategies are needed. One of the main issues is the lack of a molecular target. The
transcription factor STAT3 is constitutively active in many triple-negative breast cancers. While inhibitors of an
upstream kinase Jak2 have been tested in the clinic, they have not shown efficacy as a single therapy. STAT3
can be activated by additional kinases which may be one reason for lack of response. Therefore, we
hypothesized that targeting the activity of STAT3 may prove a useful strategy since this would target STAT3
regardless of upstream kinase. However, no STAT3 inhibitors have been approved for treatment of TNBC.
Previously, we have found that activation of the related STAT family member, STAT5, in triple-negative breast
cancer cells modulated STAT3 activity and reduced the growth and sensitized these cells to chemotherapy. This
suggests that activating STAT5 could be a treatment for TNBC. However, as STAT5 has been shown to promote
some cancers, this is not a viable option. We have found that STAT5 competes with STAT3 on DNA binding and
gene regulation, suggesting that understanding the molecular effects of STAT5 on STAT3 activity could identify
new inroads for TNBC therapy. Preliminary data from ChIP-seq analysis identifies a subset of binding regions
within the genome that both STAT3 and STAT5 bind, particularly in regulating additional transcription factors.
Directed ChIP demonstrates that while STAT3 is dominant over STAT5 on a few sites, STAT5 is dominant over
STAT3 on numerous sites. This suggests that STAT5 modulates STAT3 activity by oppositely regulating several
genes that may play key roles in TNBC, raising the possibility that targeting STAT3 via STAT5 activity could
reduce the aggressiveness of TNBC and sensitize these cancer cells to chemotherapy. We hypothesize that
defining how STAT5 modulates STAT3 may lead to new treatment strategies that mimic the effects of STAT5
on STAT3. To address this, we will carry out the following specific aims. In aim 1, we will identify genes
differentially regulated by STAT3 and STAT5 in triple-negative breast cancer. In aim 2, we will assess the
biological effects of a subset of genes that STAT5 and STAT3 both regulate in TNBC. In aim 3, we will use a
new method to identify STAT3 and STAT5 cofactors at specific loci within the genome, providing us with a more
complete understanding on the competition between STAT3 and STAT5 on gene expression. We expect to
identify both the mechanism of differential gene regulation by STAT5 and STAT3 and identify key genes that are
differentially regulated by STAT5 and STAT3 in TNBC. Identifying these genes may serve as biomarkers or
targets for future treatment of triple-negative breast cancer by mimicking the effects of STAT5 activation on
STAT3 gene regulation.
