# Investigating the Tumor Suppressor Role of miR-424(322)/503 in Breast Cancer

> **NIH NIH F31** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $5,499

## Abstract

PROJECT SUMMARY/ABSTRACT
The mammary gland is an exceptionally dynamic organ, undergoing alternating cycles of expansion and
regression over the female reproductive lifespan13,21. These highly-regulated cycles of proliferation and cell
death are dictated by the ovarian hormones and involve a massive expansion of the mammary epithelium,
supported by a transient increase in the number of mammary stem cells (MaSCs)8–10. It is well known that, in
patients, both the number of past menstrual cycles and pregnancy (transiently) increase the risk of developing
breast cancer1,2. However, the underlying cause of this phenomenon is unclear. Growing evidence, however,
suggests that improper involution, the process of tissue regression following lactation, is involved in increasing
this risk3,4. Our lab has identified the miR-424(322)/503 cluster as an important regulator of involution6, and I
have recently shown that miR-424/503 is lost in ~14% of breast cancers and that, over time, miR-
424(322)/503-/- (KO) female mice develop mammary tumors that are promoted by pregnancy7. My preliminary
analysis of human breast tumors has revealed that miR-424(322)/503-deficient breast cancers have
accumulation of β-catenin and hyperactivation of the Wnt/β-catenin signaling pathway. Female KO animals
show several hallmarks of aberrant canonical Wnt pathway activation, evidenced by the nuclear accumulation
of β-catenin as well as Keratin 6 expression. The expansion of the mammary epithelium induced by the
ovarian hormones during the estrous cycle and pregnancy is achieved via a transient increase in the number of
mammary stem cells (MaSCs) driven by activation of canonical Wnt signaling8–10. Thus, this proposal seeks to
elucidate the mechanism of miR-424(322)/503 regulation of mammary epithelial homeostasis via its effect on
MaSC expansion. In Aim 1, I will determine whether miR-424(322)/503 regulates various Wnt/β-catenin
pathway regulators using biochemical approaches. In Aim 2, I will interrogate the role of miR-424(322)/503 in
regulating its targets across various mammary epithelial cell types and stages. Finally, in Aim 3, I will study the
effect of miR-424(322)/503 loss on MaSC homeostasis in vivo. These studies seek to reveal a novel
mechanism of regulation across reproductive stages and cell types of the mammary epithelium under the
umbrella of miR-424(322)/503 regulation.

## Key facts

- **NIH application ID:** 9937681
- **Project number:** 5F31CA232691-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Erin Nekritz
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $5,499
- **Award type:** 5
- **Project period:** 2018-07-17 → 2020-09-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937681

## Citation

> US National Institutes of Health, RePORTER application 9937681, Investigating the Tumor Suppressor Role of miR-424(322)/503 in Breast Cancer (5F31CA232691-03). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9937681. Licensed CC0.

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