Functional interplay between Hippo and estrogen receptor ESR1 Project Summary/Abstract The majority of breast cancers are estrogen receptor (ER positive and growth of ER+ cancer is dependent on ER function. Hormone therapy by inhibiting ER is most commonly used for ER+ breast cancer treatment, however, drug resistance develops. There is strong medical need to develop new therapy, particularly for hormone therapy resistant breast cancer. Estrogen receptor 1 (ESR1) encodes the major form of ER and has been extensively studied for its function as a nuclear transcription factor. However, the transcriptional regulation of ESR1 itself is less understood. Preliminary studies from our laboratory have shown that ESR1 expression is tightly controlled by the Hippo pathway, which is known for its role in organ size control and tumorigenesis. Deletion of LATS1/2 kinases, core components of the Hippo pathway, abolishes ESR1 expression and inhibits growth of ER+ breast cancer cells. We further discovered that LATS1/2 suppress cancer cell immunogenicity. This proposal is based on our novel and exciting observations. A major goal of this project is to reveal the molecular mechanism of ESR1 transcription regulation by the Hippo pathway and the functional significance of ESR1 in mediating Hippo biology in breast tissue. Furthermore, we posit that LATS inhibition has two effects on ER+ breast cancer: suppression of cell growth by reducing ESR1 expression; and enhancing the efficacy of immunotherapy by increasing cancer cell immunogenicity. The second major goal is to provide scientific basis for targeting the LATS1/2 kinases as a novel therapy for ER+ breast cancer.

Narrative Estrogen receptor gene (ESR1) plays a major role in development, tissue homeostasis, and human cancer. The main goal of this proposal is to investigate the functional cross talk between ESR1 and the Hippo pathway, which is known to play a major role in organ size control and tumorigenesis. Completion of this project will not only address fundamental questions in ESR1 gene regulation and its role in Hippo biology, but also provide scientific basis for therapeutic intervention of the Hippo pathway for ESR1 expressing cancers, such as breast cancer.