Tuesday, April 1, 2025
4/1/2025
Deciphering the role of EYA3/PP2A in triple negative breast cancer metastasis - Breast cancer (BC) is one of the most diagnosed cancers in women (second only to skin cancer) and comprises ~30% of all new female cancers each year. Nearly all BC-related deaths are caused by metastatic dissemination. Triple negative breast cancer (TNBC), which is characterized by the absence of estrogen receptors, progesterone receptors, and amplification of human epidermal growth factor receptor 2 (ER/PR/HER2), is highly metastatic, with poorer short-term survival than other BC subtypes. Because of the lack of actionable targets, this subtype of BC has limited targeted therapies. Recent data suggest that TNBC is more immunogenic than other BCs, due to its higher mutational burden. However, preliminary data from immunotherapy trials have shown only modest responses in TNBC, likely because TNBC is a heterogeneous disease, and can exhibit immunoreactive or immunosuppressive tumor immune microenvironments (TIME). Thus, understanding molecular pathways that specifically contribute to TNBC are critical for developing new therapeutic avenues. In this proposal we study the role of a critical developmental transcription coactivator and phosphatase, Eya3, and its interaction with the B55α subunit of PP2A, in mediating breast cancer metastasis. Eya3 is overexpressed in TNBC when compared to other BC subtypes, and we have previously demonstrated that it enhances BC growth via a Myc-PD-L1 axis that suppresses CD8+ T-cell elimination of tumor cells. Preliminary data in this proposal demonstrate that Eya3 does not only regulate primary tumor growth, but also strongly, and specifically, regulates the TIME in the pre-metastatic niche and increases metastasis. Our preliminary data further show that in addition to stabilizing Myc, Eya3 directly regulates NFkB signaling, which is known to mediate inflammation and promote metastasis. In this proposal we will test the hypothesis that Eya3 mediates tumor progression not only by regulating Myc signaling, but also by directly regulating NFkB signaling through a shared mechanism that requires an interaction between Eya3 and PP2A-B55α and leads to an altered TIME. Understanding the molecular mechanism(s) by which Eya3 regulates PP2A function to alter two critical cancer nodes may in the future lead to novel, less toxic means to target immune suppression and metastasis in TNBC. To test this hypothesis, we will carry out two aims: 1) To determine the molecular and cellular mechanism(s) by which the Eya3-NFkB axis enhances TNBC metastasis, 2) To determine the molecular mechanism(s) by which Eya3 regulates NFkB signaling and whether this axis can be inhibited simultaneously with the Myc axis. This proposal will enable us to understand how Eya3 promotes TNBC via enhancing the tumor promotional, rather than suppressive, actions of PP2A. It will also set the stage for the exciting possibility that direct inhibition of the Eya3/PP2A-B55a interaction may be an effective means to target two major tumor promotional pathways that are difficult to target directly (Myc) or whose targeting leads to significant toxicities (NFkB), as a means to enhance the adaptive and innate immune response to TNBC.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).