Contribution of ERa/PR Crosstalk to Endocrine Therapy Resistance in the Context of ERa-Y537S

PROJECT SUMMARY/ABSTRACT Half of estrogen receptor (ER?)-positive breast cancer patients treated with endocrine therapies manifest intrinsic or acquired therapy resistance. One-third of these patients present with metastatic tumors containing ER? Y537S mutations. This mutation results in constitutive activity of ER? and altered ER?-associated gene expression.

Previous research suggests that ER? and the progesterone receptor (PR) engage in complex interactions involving reciprocal regulation of ER? and PR transcription factor activity known as ER?/PR crosstalk.

Thus, there may be therapeutic value in targeting both nuclear receptors simultaneously in ER?/PR-positive breast cancers. However, preliminary data suggests that ER?/PR crosstalk is altered in the context of ER? Y537S, likely contributing to therapy resistance. Although the constitutive activity associated with ER?

Y537S and the efficacy of combined ER?/PR therapies have independently been assessed, there has yet to be characterization of the effects of ER?

Y537S on ER?/PR crosstalk or the specific effects of ER?/PR-targeted therapies on ER?/PR crosstalk in the context of ER? Y537S. The objective of this proposal is to determine the effects of the most commonly occurring, treatment-resistant ER?

Y537S mutation on ER?/PR crosstalk and resultant transcriptional activity, and to elucidate how this unique interaction leads to endocrine therapy resistance in ER?- positive breast cancer. Previous research identified a synergistic effect of combined ER?/PR antagonism in ER? WT cancer cells, where combined treatment results in tumor regression in vivo.

Conversely, preliminary data suggests that treatment of ER? Y537S tumors with combined ER? and PR antagonists results in significantly increased tumor proliferation in vivo. As previous research has highlighted a significant alteration in gene expression associated with ER?

Y537S, it is likely that changes to both ER?- and PR-driven gene expression drive the altered response to ER? and PR antagonists. My central hypothesis is that ER?

Y537S alters the transcription factor activity of ER? and PR, causing dysregulation of gene expression in SERM-resistant breast cancer. This hypothesis will be assessed with the following Specific Aims: 1. Determine how the activating ER? Y537S point mutation affects ER? transcriptional activity and alters ER?/PR crosstalk. 2.

Assess the efficacy of various selective estrogen and progesterone receptor modulators (SERMs and SPRMs) in treating patient-derived models of ER? Y537S tumors. Understanding the role of ER?

Y537S in altering gene expression and reducing the response to SERM and SPRM treatment will provide understanding as to why these tumors are resistant to standard-of-care treatment and will additionally suggest alternative targets for treatment.