# Using Cultured Human Mammary Epithelial Cells to Explore the Role of the Yap Oncogene in Early Breast Cancer Progression

> **NIH NIH F32** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2020 · $65,310

## Abstract

Yap is an oncogene implicated in the progression of many cancers. However, most research on Yap
oncogenic function has been performed in immortalized cell lines that have already undergone many
steps of malignant progression. This study will use a HMEC cell culture system that closely models
the early steps of breast cancer progression in vivo to understand the function of Yap during early
breast cancer progression. Particular emphasis will be place on examining Yap’s role in the crucial
step of reactivating telomerase to overcome the replicative senescence barrier, a process that we
have shown proceeds in two steps. First Yap causes a change permissive for the acquisition of
immortality (termed conditional immortality). Then, the HMEC then need to undergo a variable
process (termed conversion) to convert their telomere maintenance mechanisms to support the short
stable configuration seen in cancer cells. Preliminary data has led to the following hypothesis: Yap
dysregulation during early breast cancer progression alters gene expression and causes cells to be
susceptible to acquire cancer properties including conditional immortality and cancer stem cell
characteristics. This proposal will rigorously test this hypothesis with three aims. (1) The Yap targets
that promote a state permissive for the acquisition of conditional immortality will be determined by
performing RNAseq and differential gene expression analysis. (2) Yap induction of cancer stem cell
properties early in immortalization will be examined with three assays: qPCR of RNA’s involved in
stem cell phenotypes, drug resistance, and formation of mammospheres in 3D culture. The genes
downstream of Yap dysregulation that promote these stem cell phenotypes will also be determined.
(3) the breast cancer stages in which Yap induces breast cancer progression will be defined by
obtaining tissue from normal, DCIS, and increasing breast cancer stages and performing
immunofluorescence using antibodies that detect Yap and genes identified in aims 1 and 2 that
promote immortalization and cancer stem cell phenotypes. Furthermore, published transcriptome and
microarray datasets will be used to determine if Yap and immortalization and cancer stem cell
inducing genes downstream of Yap are increased in specific stages of breast cancer. The
experiments outlined in this proposal will determine the function of Yap dysregulation during early
breast cancer progression and may identify novel therapeutic targets to prevent breast cancer by
preventing the immortalization step. The Yap oncogene is implicated in many cancers and
immortalization is a barrier in the early progression of most human carcinomas; therefore these novel
therapeutic targets could also be relevant to the prevention of most human carcinomas.

## Key facts

- **NIH application ID:** 10240976
- **Project number:** 7F32CA247311-02
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Tara Micole Fresques
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 7
- **Project period:** 2020-09-29 → 2023-09-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240976

## Citation

> US National Institutes of Health, RePORTER application 10240976, Using Cultured Human Mammary Epithelial Cells to Explore the Role of the Yap Oncogene in Early Breast Cancer Progression (7F32CA247311-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10240976. Licensed CC0.

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