Jung-Yoon Yoo

ERBB2 Targeting Reveals a Significant Suppression of Tumorigenesis in Murine Endometrial Cancer with Pten Mutation

Endometrial cancer is the most common gynecologic malignancy. PTEN is a negative regulator of PI3K signaling and is deficient in > 50% of primary human endometrial cancer. Amplification of ERBB2 promotes tumorigenesis and pathogenesis of several human cancers. However, the effect of ERBB2 targeting has not been studied in endometrial cancer with PTEN mutations. The murine model Pgr

ARG1 Is a Potential Prognostic Marker in Metastatic Endometrial Cancer

Endometrial cancer (EC) is the most common gynecologic malignancy. While the majority of patients present with early-stage and low-grade EC and have an excellent prognosis, a subset has metastatic disease at presentation or develops distant recurrence after initial treatment of the primary. However, the lack of prognostic biomarkers for metastatic EC is a critical barrier. Arginase 1 (ARG1) regulates the last step of the urea cycle, and an increase in ARG1 has been correlated as a poor prognostic factor in a variety of cancers. In the present study, ARG1 expression was evaluated as a potential prognostic marker for metastatic EC in endometrial hyperplasia and cancer of mice with Pten mutation as well as Pten and Mig-6 double mutations. While Pten mutation in the uterus is not sufficient for distant metastasis, mice with concurrent ablation of Mig-6 and Pten develop distant metastasis. Our immunostaining and RT-qPCR analysis revealed that the expression of ARG1 in early stage of EC as well as endometrial hyperplasia from mice deficient in Mig-6 and Pten mutations significantly increased compared to Pten mutation in the uterus. The results suggest that a high level of ARG1 is associated with poor prognosis in association with EC of mouse.

MIG-6 Regulates HDAC1-Mediated Angiogenesis and Tumorigenesis in PTEN-Deficient Endometrioid Endometrial Cancer

Abstract Endometrioid endometrial cancer (EEC) is the most prevalent gynecologic malignancy, yet no targeted therapies are currently approved by the FDA specifically for it. To identify therapeutic targets for EEC, we performed transcriptomic and proteomic analyses in genetically engineered preclinical cancer models, including uterine-specific phosphatase and tensin homolog (Pten)-deficient (Ptend/d) mice and Ptend/d mice with additional overexpression of the tumor suppressor mitogen-inducible gene 6 (Mig-6) that develop EEC. Transcriptomic analysis revealed significant inhibition of immune, inflammatory, and angiogenesis pathways, with hypoxia-inducible factor-1α (HIF1α) as a key upstream regulator. Interactome and immunoprecipitation analyses identified HDAC1 as a MIG-6–interacting protein that mediates angiogenic signaling in PTEN-deficient endometrial cancer. MIG-6 overexpression suppressed HDAC1 activity and downstream HIF1α-driven angiogenesis. Pharmacologic inhibition of HDAC1 with panobinostat recapitulated the tumor-suppressive effects observed with MIG-6 overexpression. These findings suggest that HDAC1 may represent a potential therapeutic target in EEC and that HDAC inhibition can attenuate early tumor progression and angiogenic signaling in preclinical models. Implications: This study identifies the MIG-6–HDAC1 axis as a key regulator of angiogenesis in EEC, highlighting HDAC1 inhibition as a promising targeted therapeutic strategy for early tumor suppression.