Project Summary/Abstract
Estrogen receptor positive (ER+) breast cancer (BC) accounts for the majority of all diagnosed BC for women
in the United States. While traditional antihormone therapies for ER+ BC are initially effective, approximately
40% of ER+ BC will develop therapy resistant recurrence and metastasis, which contributes to most BC related
deaths. The presence of the G-protein coupled estrogen receptor (GPER) is suggested to aid in disease
progression and metastasis of BC and GPER is theorized to be a driver of therapy resistance due to the
agonistic activity of tamoxifen, a traditional antihormone therapy for ER+ BC. GPER is expressed on cancer-
associated fibroblasts, the main remodelers of the extracellular matrix (ECM) which plays an important role in
disease progression. Previous work by Dr. Suzanne Ponik and collaborators has demonstrated dynamic
interactions between hormone signaling and ECM stiffness to drive tumor cell invasion and metastasis.
However, the mechanism responsible for these dynamic interactions is poorly understood. Therefore, the
hypothesis for the proposed research is that GPER activated CAFs are priming the TME to drive
tamoxifen resistant disease progression in ER+ BC. The research strategy proposes to establish the
specific role GPER activated CAFs play on ECM protein deposition and organization in vitro prior to introducing
GPER knockdown CAFs into an orthotropic ER+, tamoxifen resistant tumor model. The in vitro and in vivo
work will be complemented with a novel tumor microarray (TMA) from BC patients where the association
between GPER expression, ECM signatures, administered therapy and patient outcome can be validated. The
specific aims of this proposal are: 1) identify how GPER signaling in CAFs regulates biophysical/biochemical
cues and how GPER-mediated matrix deposition influences tumor cell behavior in vitro, 2) test the hypothesis
that ECM stiffness and antihormone therapy synergize through GPER signaling in CAFs to drive tumor
progression in vivo, and 3) define how GPER expression and ECM signatures relate to human disease/patient
outcomes. The research training for this proposal will be conducted under the co-sponsorship of Dr. Suzanne
Ponik (Sponsor) and Dr. Mark Burkard (Co-Sponsor) at the University of Wisconsin-Madison. Both Dr. Ponik
and Dr. Burkard will provide mentorship on the research conducted by Shelby Fertal as well as provide
guidance for her career development with the intention that Shelby will remain in academia. The success of
this proposal will offer novel insights into the mechanisms of antihormone therapy driven disease progression
in ER+ BC and provide a solid foundation for Shelby’s career as an independent research professor.
