# Non-canonical FADD signaling as a genetic driver of invasive lobular carcinoma

> **NIH NIH K99** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $128,012

## Abstract

Project Summary/Abstract
Research: Invasive lobular carcinoma (ILC) is a unique histological subtype of breast cancer that has chronically been
understudied. The long-term goal of the proposed research project is to credential non-canonical FADD signaling as a
genetic driver of ILC. Based on its high expression/amplification in human ILC cell lines, tumors and metastatic samples
and its association with poor survival, I hypothesize that FADD is a key mediator of ILC disease progression and a
novel therapeutic target to improve patient outcomes. I will test this hypothesis through the following specific aims:
Aim 1: Investigate the functional role of non-canonical FADD in ILC biology
In contrast to its death-related cytoplasmic functions, nuclear FADD plays a non-canonical pro-survival role. This aim
will couple RNAi and CRISPR loss-of-function approaches with viral overexpression in human ILC cell lines to assess
the role of FADD in cell proliferation, cell cycle progression, cell survival and suppression of autophagy. In addition, I
will perform functional experiments to assay the requirement for FADD in cell adhesion, migration and invasion.
Aim 2: Characterize the non-canonical FADD signaling axis in ILC cell lines
FADD translocates to the nucleus upon phosphorylation at Serine 194 by CK1α and FIST/HIPK3 kinases, leading to
downstream activation of NF-κB and mTOR pathways. To dissect this FADD signaling cascade, I will combine genetic
manipulation via RNAi and CRISPR with pharmacological inhibitors. In addition, I will identify ILC-specific components
of this cascade through RNA-Sequencing, protein arrays and Mass Spectrometry approaches.
Aim 3: Determine the prognostic and therapeutic significance of FADD in ILC tumors and explants
This aim will initiate translation of this project toward clinical application. I will assay FADD and phosphorylated-FADD
protein expression and correlate with clinical outcome in human ILC samples. Using innovative ex vivo tumor explants
and novel xenograft mouse models of human ILC cell lines, I will evaluate the anti-tumor and anti-metastatic effects of
genetic and pharmacological inhibitors of the FADD signaling axis combined with endocrine therapy.
Career Development, Goals and Environment: This research project will be carried out under close guidance of my
mentor Dr. Steffi Oesterreich, an international leader in ILC research, and in frequent interactions with clinicians,
pathologists, patient advocates and biostatisticians, which will provide me with a unique, well-rounded training
opportunity. Collaborations with Dr. Alnawaz Rehemtulla and Dr. Lukas Dow will provide a critical experience on the
non-canonical FADD signaling pathway and genetic editing via CRISPR, which has not previously been a component of
my training. While ensuring successful execution of the research aims in this proposal, this training will also provide a
unique direction for my independent research career. The dedicated guidance I wil...

## Key facts

- **NIH application ID:** 9995446
- **Project number:** 5K99CA237736-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Nilgun Tasdemir
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $128,012
- **Award type:** 5
- **Project period:** 2019-09-01 → 2020-12-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9995446

## Citation

> US National Institutes of Health, RePORTER application 9995446, Non-canonical FADD signaling as a genetic driver of invasive lobular carcinoma (5K99CA237736-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9995446. Licensed CC0.

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