# Control of quiescence and outgrowth in latent breast preneoplastic cells

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2020 · $350,040

## Abstract

PROJECT SUMMARY / ABSTRACT
A critical stage in early breast tumorigenesis is the emergence of preneoplastic cells that carry key tumor
drivers but remain in a latent state similar to normal quiescent cells. Such latent preneoplastic cells have been
reported in precancerous lesions and tissues surrounding tumors, and are implicated as precursors for primary
and recurrent or second field tumors. Despite advances in detection, little is known about the properties of
preneoplastic cells to predict or prevent tumor formation. Our long-term goal is to understand the cellular
controls in preneoplastic cells and to exploit these controls for developing novel prognostic markers and tumor
prevention strategies. The quiescence and outgrowth of latent preneoplastic cells has important implications in
driving tumor formation. Here, we propose to investigate this proliferative control in preneoplastic breast cells
with hyperactivated AKT signaling, a major tumor driver found in early lesions of the breast and many other
epithelial tissues. A major barrier to studying latent preneoplastic cells at a quiescent state is the lack of
experimental models. To overcome this, we recently devised specialized organoid and in vivo models of
quiescent preneoplastic cells by inducing oncogenic alterations in growth-arrested 3D organoids of non-
transformed human mammary cells and by direct engineering cells in intact mouse mammary glands. Using
these models, we recently reported that aberrant AKT activation in preneoplastic breast cells induces a primed
quiescent cell state that maintains growth arrest under normal conditions, but promotes selective proliferation
in tumor-promoting microenvironments. To gain insight into this cell state, our preliminary studies revealed a
unique cell cycle program with concurrent upregulation of cell cycle inhibitor, p57Kip2 (p57), and promoter,
cyclin D1. This increase in p57 protein abundance is also evidence in AKT-induced preneoplastic cells in mice.
Notably, we found that attenuating this AKT-induced p57 upregulation is sufficient to drive these quiescent
preneoplastic cells to proliferate and that downregulation of p57 protein level is linked to proliferative outgrowth
in tumor-promoting microenvironments. These findings lead us to hypothesize that a p57-mediated cell cycle
program controls the maintenance and outgrowth of a primed quiescent state induced by AKT in latent breast
preneoplastic cells. We propose three aims to 1) define the molecular identity and induction mechanism of this
AKT-induced cell cycle program, 2) elucidate the regulatory role of p57 in the proliferative control of these
quiescent preneoplastic cells, and 3) determine the role of p57 in mediating mammary preneoplastic
development in mice. These studies will reveal the functional role and the underlying mechanism, as well as
provide insights into the prognostic value, of p57 in the progression of preneoplastic breast lesions with
aberrant AKT activation. More b...

## Key facts

- **NIH application ID:** 9875265
- **Project number:** 5R01CA200652-04
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Cheuk Tung Leung
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $350,040
- **Award type:** 5
- **Project period:** 2017-03-06 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9875265

## Citation

> US National Institutes of Health, RePORTER application 9875265, Control of quiescence and outgrowth in latent breast preneoplastic cells (5R01CA200652-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9875265. Licensed CC0.

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