Our lab has previously identified a mechanism of transforming growth factor beta (TGFß)-mediated
epithelial-to-mesenchymal transition (EMT) in murine mammary epithelium. We have shown that expression of
the interleukin-like EMT inducer (ILEI) protein is necessary to induce EMT in murine mammary gland cells
following exposure to TGFß. ILEI has also been shown to increase the self-renewal capacity of epithelial cells
following EMT, through its interaction with leukemia inhibitory factor receptor (LIFR), suggesting that the
ILEI/LIFR signaling axis promotes breast cancer stem-cell (BCSC) phenotype. Further, our lab has shown that
TGFß-induced upregulation of LIFR is ILEI-dependent. In cells derived from a mouse tumor progression model
created by our lab, spheroid formation capacity in non-adherent cell culture conditions is attenuated following
either ILEI or LIFR knockdown. Additionally, orthotopic grafts of cells with ILEI or LIFR knockdown display a
decrease in tumor growth and metastasis relative to control cells. We hypothesize that TGFß-induced LIFR
regulation contributes to metastases.
The precise mechanisms of ILEI-mediated EMT and BCSC induction are unknown. Herein we aim to
interrogate ILEI/LIFR axis-mediated mechanisms downstream of TGFß exposure that influence (1) the regulation
of LIFR protein expression and (2) the ensuing maintenance of self-renewal capacity and disease progression
in our model. In Specific Aim 1, the LIFR promoter sequence will be examined to identify key factors regulating
LIFR expression. In Specific Aim 2, transcriptomic data will be examined following ILEI/LIFR knockout to identify
a signature of ILEI/LIFR-regulated gene expression and its association with self-renewal capacity. In Specific
Aim 3, the role of LIFR will be examined in vivo to determine the impact of its expression upon outgrowth of
pulmonary tumors following tail vein injection of cells into immunodeficient mice.
Data from our experiments will characterize a signaling pathway associated with BCSC maintenance and
will potentially identify novel therapeutic targets. Our findings may translate to novel treatments for dormancy
and relapse in human metastatic breast cancer.