# Uncovering the basis and implications of lineage plasticity in breast cancer

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $342,550

## Abstract

Tumorigenesis involves the accumulation of genetic aberrations, leading to the emergence of
distinct clonal subpopulations. Studies that have tracked the evolution of genetic events within
and between these clonal populations have provided deep insights into the process of
tumorigenesis and response to therapy. Despite these advances, the process of metastasis,
which is responsible for over 90% of cancer-related deaths, remains poorly understood. The
majority of studies that compare genetic aberrations between the primary tumor and metastases
find few alterations that are unique to the metastatic clone. Indeed, there are no known
recurrent genetic drivers of metastasis. In contrast to primary tumor initiation and establishment,
my own future research directions hypothesize that the process of metastasis does not rely on
the further acquisition of novel genetic alterations beyond those needed to form primary tumor
cells, but is instead driven by alterations to the chromatin landscape, presenting itself in the form
of cellular plasticity and a reprogrammed cell state. We have uncovered evidence of a luminal-
to-basal transition (LBT) in breast cancers of the luminal B molecular subtype. The LBT is
essential for tumor progression as tumors that do not exhibit this plasticity show attenuated
metastatic ability and are more sensitive to chemotherapy. Based on these data we hypothesize
that the acquisition of tumor cell plasticity that allows breast cancer cells to stray from their
lineage-of-origin is an essential first step to initiating the metastatic cascade and disease
progression. This increased plasticity likely propels cells into a state that is highly adaptive to
new habitats and responsive to interactions with components of the tumor microenvironment, all
of which are critical to the process of metastasis. We propose to test this by elucidating the
effects of the LBT in luminal B breast cancers by assessing the stability of the cells that undergo
the transition, their tumor-initiating capacity and metastatic potential (aim 1). We will further
uncover the mechanisms driving the transition by studying the role of Sox4 in the emergence of
the basal cells of luminal origin, tracking its expression and determining its genome-wide
occupancy to reveal changes to its target gene repertoire during metastatic progression (aim 2).
We then propose to test the principle of tumor differentiation as a potential adjuvant to
chemotherapy by either combinatorial activation of Gαs R201C/fl and chemotherapy administration,
or by sequential activation of Gαs R201C/fl followed by chemotherapy administration.

## Key facts

- **NIH application ID:** 10768613
- **Project number:** 5R01CA267691-04
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Todd W. Miller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $342,550
- **Award type:** 5
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10768613

## Citation

> US National Institutes of Health, RePORTER application 10768613, Uncovering the basis and implications of lineage plasticity in breast cancer (5R01CA267691-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10768613. Licensed CC0.

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