# The Role of Dedifferentiation in Basal like Breast Cancer

> **NIH NIH F31** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2024 · $53,974

## Abstract

ABSTRACT
The adult mammary gland is maintained by unipotent progenitor populations which are derived
from multipotent stem cells exclusive to embryonic development. The emergence of multipotency
caused by oncogenic mutations in adult glands is a common process in malignant breast cancer
transformation that enables cellular plasticity and promotes tumor heterogeneity. Although these
processes pose immense therapeutic challenges for aggressive undifferentiated breast cancers
such as Basal-like Breast Cancer (BLBC), the most common Triple Negative Breast Cancer
(TNBC), the mechanisms underlying cellular plasticity in the adult mammary gland remain poorly
understood. The BLBC founder cell (BFC) is likely of the ER- luminal lineage as suggested by
multiple groups, however concrete evidence to prove this notion is lacking. In this proposal, we
seek to identify and characterize the BFC and to uncover mechanisms responsible for
multipotency reactivation in these cells. We hypothesize that a transformation competent
unipotent luminal progenitor acquires multipotency through a conserved pathway or gives rise to
multipotent progeny that undergo stepwise reprogramming essential for BLBC tumor progression.
To test this hypothesis, I have performed single cell RNA sequencing of hyperplastic mammary
glands in the C3/Tag BLBC mouse tumor model to (1) establish candidate BFC populations by
integrating epithelial clustering data with RNA velocity and pseudotemporal analysis of cell
populations, (2) determine the role of suspected BFC clusters in mammary gland and tumor
development, and finally (3) identify the molecular determinants of dedifferentiation in the BFC.
Findings from the analysis of this data and from follow up lineage tracing experiments will reveal
the BFC in the highest resolution to date as well as pathways involved in its transformation and
subsequent dedifferentiation. A detailed understanding of aberrant dedifferentiation in BLBC may
be useful for improving the state of current and future BLBC treatments and for treatment of other
aggressive cancers that employ cellular plasticity for treatment resistance and evasion. Under the
proven mentorship and expertise of Dr. Wenjun Guo, I will execute the research and training plan
outlined in this proposal. This, combined with the training environment provided by the Albert
Einstein College of Medicine will allow me to contribute to the fields of breast cancer and stem
cell biology and to develop the research and professional skills necessary to become an
independent physician-scientist.

## Key facts

- **NIH application ID:** 10925261
- **Project number:** 5F31CA271757-03
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Jessie Larios-Valencia
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 5
- **Project period:** 2022-09-28 → 2026-09-27

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10925261

## Citation

> US National Institutes of Health, RePORTER application 10925261, The Role of Dedifferentiation in Basal like Breast Cancer (5F31CA271757-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10925261. Licensed CC0.

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