# Interplay of mammary luminal cells and environmental factors in establishing p53-deficient premalignant field

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $374,766

## Abstract

Premalignant field often refers to histologically normal epithelial cells surrounding a tumor that carry some of
the same genetic and/or epigenetic changes as in the tumor. Such cells and tumor cells surrounded by
them may have a common clonal origin. A premalignant field can be formed upon its cell-of-origin acquiring
a clonal growth advantage over its neighbor cells. Normally clonal competition between equipotent
epithelial cells is neutral. However, some genetic mutations can tilt the neutral competition so that the
mutated cells have increased “fitness” and a higher chance to replace their neighbors, whereas other
mutations can only do so upon interaction with environmental modifiers. A better understanding of how the
interplay of genetic, epigenetic and environmental factors tilts the stochastic process of neutral clonal
competition is the key for understanding how premalignant field is formed and how it can be targeted. p53
mutation is the most common mutation in human breast cancer and represents an early event in breast
tumorigenesis. By inducing p53-loss in a small number of Keratin 8+ luminal mammary epithelial cells
(MECs), we observed a premalignant field comprised of p53-deficient luminal MECs; mammary tumors later
emerged from it with 100% penetrance. Since constitutive p53 knockout mice have a largely normal MEC
phenotype, we hypothesize that this p53-deficient luminal premalignant field is formed upon interplay of
p53-mutant luminal MECs and environmental factors (e.g., ovarian hormones, immune cells). As
proliferation, differentiation and apoptosis of MECs are controlled by cyclic ovarian hormones, Aim 1 will
determine if induced p53-deficiency in estrogen receptor (ER)+ or ER- luminal MECs triggers an imbalance
of proliferation versus apoptosis between p53 mutant cells and their wild-type neighbors, resulting in a net
accumulation of p53-deficent luminal cells over time, in an estrous cycle-dependent manner. Aim 2 will
further determine the role of cyclic changes of ovarian hormones in establishing the p53-deficient luminal
premalignant field, by ovariectomy, hormone (estrogen, progesterone) replacement, and tamoxifen
treatment. Expression profiling of p53-deficient luminal MECs revealed a unique immune-related signature
suggestive of immunosuppression; our preliminary study further demonstrated that M2-polarized
macrophages could enhance growth of luminal MECs. Based on these data, Aim 3 will investigate potential
roles of various immune cell types, in particular, macrophages (e.g., M2-polarized), in shaping the p53-
deficient luminal premalignant field. Overall, a better understanding of how interaction of the hormone
milieu and immune cells in the mammary gland with p53-mutant luminal MECs contributes to development
of this p53-deficient premalignant field is expected to lead to novel strategies of breast cancer prevention,
particular in high-risk populations (e.g., Li-Fraumeni syndrome patients). The idea and approach propos...

## Key facts

- **NIH application ID:** 9828545
- **Project number:** 5R01CA222560-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Zhe Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $374,766
- **Award type:** 5
- **Project period:** 2017-12-12 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828545

## Citation

> US National Institutes of Health, RePORTER application 9828545, Interplay of mammary luminal cells and environmental factors in establishing p53-deficient premalignant field (5R01CA222560-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828545. Licensed CC0.

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