# Novel Mechanisms of Nuclear Phosphoinositide Signaling in Regulation of the YAP/TAZ Pathway in Triple-negative Breast Cancer

> **NIH NIH P20** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $368,849

## Abstract

Phosphoinositides (PIs) are lipid messengers that control many aspects of human physiology. A significant 
fraction of PIs (>40% of total PIs) is found in the nucleus, however the nature and functions of the nuclear 
PIs are largely unknown. We discovered that phosphatidylinositol 4,5-bisphosphate (PI4,5P2) is an 
abundant PI species in the nucleus and the PI4,5P2-generating kinase phosphatidylinositol-4-phosphate-5- 
kinase type 1 alpha (PIPKI􀁄) is a major enzyme modulating nuclear PI4,5P2 signaling. Nuclear PI4,5P2 can 
be further phosphorylated by a nuclear-localizing PI3-kinase (PI3K) inositol phosphate multikinase (IPMK) 
to produce a PI species, PI3,4,5P3, that has been implicated in oncogenesis. This suggests that PIPKI􀁄 
and IPMK are potential targets for cancer therapy. Consistently, we showed that depletion or 
pharmacological inhibition of PIPKI􀁄 and IPMK leads to cancer cell death by apoptosis in triple negative 
breast cancer (TNBC) cells. Moreover, in TNBC cells, we discovered that depletion of PIPKI􀁄 and IPMK 
significantly reduces the expression of YAP/TAZ target genes that have established contributions to 
oncogenesis. TNBC is the most aggressive subtype of breast cancer and associated with poor patient 
survival due to lack of alternatives to current chemotherapies. As a result, there is an urgent need for 
discovering novel targeted therapeutics in TNBC. The YAP/TAZ-PI kinases (PIPKI􀁄 and IPMK) pathways 
are attractive drug targets because aberrant activation of YAP/TAZ is frequently found in breast cancer 
particularly in TNBC, PIPKI􀁄 gene is commonly amplified in TNBC, and the nuclear PI3,4,5P3 pathway is 
frequently deregulated in TNBC. Precise understanding of nuclear PIs-mediated YAP/TAZ pathway will 
provide knowledge which can be utilized for developing targeted therapeutics against TNBC. In this 
proposal, we will 1) elucidate molecular mechanisms by which the YAP/TAZ pathway is controlled by 
PIPIK􀁄 and IPMK via extensive biochemical and cell biological approaches and 2) investigate contributions 
of PIPIK􀁄 and IPMK in TNBC pathogenesis in cultured TNBC cells and mouse models.

## Key facts

- **NIH application ID:** 10579376
- **Project number:** 5P20GM121316-05
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Suyong Choi
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $368,849
- **Award type:** 5
- **Project period:** 2022-03-01 → 2023-07-19

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10579376

## Citation

> US National Institutes of Health, RePORTER application 10579376, Novel Mechanisms of Nuclear Phosphoinositide Signaling in Regulation of the YAP/TAZ Pathway in Triple-negative Breast Cancer (5P20GM121316-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10579376. Licensed CC0.

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