# Understanding expression and signaling of sex hormone receptors in brain cancers

> **NIH NIH F99** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $48,717

## Abstract

PROJECT SUMMARY
There is significant evidence of cancer-type specific patterns of sex hormone receptor expression and signaling
in many central nervous system (CNS) tumors, often correlating with their high sex-specificity. This supports the
hypothesis that sex hormone receptors play tumorigenic and pathologic roles across many CNS cancers.
However, their mechanistic functions in CNS tumors remain largely unknown. This proposal seeks to address
these knowledge gaps in 2 of these cancers: meningioma and glioblastoma (GBM). In Aim 1, I explore the
mechanism underlying progesterone receptor (PR) expression and signaling in meningiomas, the most common
primary intracranial tumors. Meningiomas are 2.7 times more common in females than in males, can arise in the
setting of exogenous female hormone therapy, and 70% express high levels PR, suggesting female sex
hormones may drive meningioma tumorigenesis. Using human meningioma xenografts in mice treated with
clinically relevant doses of synthetic progestins, I developed a model of female sex hormone-driven meningioma.
The data presented in this application suggest progestins induce PR expression, increase tumor growth, and
reduce survival through a positive feedback mechanism that requires progesterone membrane component 1
(PGRMC1), a non-classical hormone receptor with pathologic roles in breast and endometrial cancers. The
central hypothesis of my doctoral dissertation project is that progestin ligand activates PGRMC1 to drive
expression of PR in meningioma through regulation of NFB transcriptional activity, and that PR drives
meningioma growth through cytoplasmic activation of MAPK signaling and transcriptional activation of TNFSF11,
TGFA, and IRS2. Through the remainder of my graduate work I will (i) validate the pathway through which
PGRMC1 drives PR expression through ChIP-QPCR, luciferase reporter, and loss-of-function validation models,
(ii) identify hormonal cofactors involved in PGRMC1 signaling, (iii) validate the roles of PR downstream targets
in driving growth and proliferation in meningioma through gain- and loss-of-function models, and (iv) incorporate
human proteomic data to define expression levels of proteins implicated in PR and PGRMC1 signaling pathways
in human patients. In Aim 2, I outline the proposed direction of my postdoctoral studies, the characterization of
sex hormone signaling pathways in GBM. The most malignant primary brain tumors in adults, GBM are often
marked by high expression of androgen and estrogen receptors, yet limited and often contradictory functional
data for these receptors in GBM has impeded the development of sex hormone-targeted therapeutics. For this
project, I plan to (i) perform integrated proteomic and phospho-proteomic characterization of hormone signaling
networks in GBM, (ii) characterize and mechanistically validate the pathways through which sex hormone
signaling influences GBM pathology, and (iii) develop combination therapies targeting these si...

## Key facts

- **NIH application ID:** 10990437
- **Project number:** 1F99CA294312-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Martha Addison Dwyer Cady
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,717
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10990437

## Citation

> US National Institutes of Health, RePORTER application 10990437, Understanding expression and signaling of sex hormone receptors in brain cancers (1F99CA294312-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10990437. Licensed CC0.

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