# FOXL2 in Adult Granulosa Cell Tumorigenesis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $354,197

## Abstract

PROJECT SUMMARY
Adult Granulosa Cell Tumors (aGCTs) account for about 1 in 20 ovarian cancers, forming from the hormonally
active follicle resident cells responsible for ovulation. AGCTs are treated with debulking surgery, with the
possibility of pelvic radiation. There is no standard systemic chemotherapy. Recurrence frequently comes a
decade after diagnosis, with treatment left to the discretion of the attending oncologist. FOXL2 is an
evolutionarily conserved member of the forkhead transcription factor family and is essential for gonadal
development. More than 100 compromising mutations in the FOXL2 gene promote ovarian dysfunction and
craniofacial misdevelopment. In striking contrast, a single somatic mutation, FOXL2C134W, occurs nearly
universally in aGCTs, as examined across more than 400 patients of various ethnicities. We show that this
FOXL2 gene, which is uniquely found in granulosa cell tumors, is active and potent. However, the molecular
basis underlying the oncogenic effect of FOXL2C134W remains unclear, and nothing is known about the role of the
mutation in vivo. Patients present with aGCTs at or just past menopause, suggesting an initiating circumstance
that fosters tumor development. They are commonly treated with surgery and with the same chemotherapy
offered to other unrelated types of ovarian cancer. Patients who present with advanced disease, or who recur,
do poorly. An increased understanding of aGCT may provide insights for the treatment of these women. This
proposal, submitted by two collaborating PIs who are experts in studying ovarian endocrine function (Shimasaki)
and tumor formation and progression (Stupack), consists of two complementary aims to understand the role of
FOXL2C134W in tumorigenesis. Aim 1 will evaluate the effects of in situ expression of FOXL2C134W or FOXL2C130W
(the mouse equivalent) on GC function within intact and accessible follicles ex vivo using isolated mouse follicle
organoid cultures. In Aim 2, we will directly test the sufficiency of FOXL2C134W expression for tumorigenesis, via
expression of this gene selectively GCs at an adult stage of live mice. If so, this would be the first model to
directly prove causality of this mutation and should offer new opportunities for intervention.

## Key facts

- **NIH application ID:** 10401465
- **Project number:** 5R01CA244182-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** SHUNICHI SHIMASAKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $354,197
- **Award type:** 5
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401465

## Citation

> US National Institutes of Health, RePORTER application 10401465, FOXL2 in Adult Granulosa Cell Tumorigenesis (5R01CA244182-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10401465. Licensed CC0.

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