KMT2D loss redirects estrogen signaling toward… (F31CA314066) – Project Grant to Wayne State University

Abstract: Abstract the incidence of endometrial cancer is rising, especially among premenopausal women. This trend is driven in part by obesity-related hormonal imbalances-such as estrogen production through aromatase in peripheral adipose tissue. These hormone imbalances are especially relevant to endometrioid adenocarcinoma, the most common subtype of endometrial cancer, which is defined by estrogen receptor (ER) expression and near- universal activation of the phosphoinositide 3-kinase (PI3K) pathway-highlighting the need to understand how hormonal and oncogenic signaling intersect in this disease. Studies in ER+ breast cancer have shown that estrogen activates PI3K signaling through both genomic and non- genomic mechanisms. Furthermore, KMT2D, a histone methyltransferase, plays a pivotal role in facilitating estrogen-PI3K crosstalk by maintaining enhancer accessibility. However, the regulatory mechanisms behind their interaction in the endometrium are poorly understood and cannot be assumed to follow the same patterns as those in breast cancer, especially given tissue-specific hormone responses and frequent KMT2D loss-of- function mutations in endometrial cancer. In fact, our preliminary data suggest that KMT2D's role in the endometrium is to distribute estrogen signaling outputs among survival pathways, like PI3K and mapk. Thus, i hypothesize that loss-of-function mutations in KMT2D lead to redistribution of estrogen signaling outputs toward PI3K signaling, which enhances tumor survival and progression, but creates a selective dependency that can be therapeutically exploited. By defining this mechanism, the proposed research addresses a growing cancer burden in all women and could inform the development of targeted, fertility-conserving therapies for those of reproductive age. To investigate this, i will analyze transcriptomic data from RE-expression and knockout cell lines and map shifts in ERΑ binding and chromatin accessibility using cut & run and atac-SEQ (aim 1). Under the mentorship of DRS. Wilson and yang, i will develop expertise in chromatin biology, which is essential for extracting meaning from these epigenetic effects. This work will be complemented by expanding my training in biostatistics and bioinformatics with DRS. Dyson and tarca, enabling rigorous and precise integration of large-scale omics data. I will also benefit greatly from guidance in pharmacology and preclinical models. DR. Podgorski's knowledge of pharmacology and hormone driven cancer will help me explore how KMT2D loss influences tumor responses to FDA-approved agents, while DR. Polin will provide support in using mouse models to validate therapeutic vulnerabilities (aim 2). To ensure i grasp how to translate such work, DR. Winer will provide exposure to investigator-initiated trials in gynecologic oncology, illustrating how similar findings advance toward clinical application. This fellowship project, supported by the exceptional training environment at wayne state and the karmanos cancer institute, will provide the training necessary for me to advance towards independence.

KMT2D loss redirects estrogen signaling toward PI3K dependency in endometrial cancer

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