# The role of the mitochondrial unfolded protein response (UPRmt) in the etiology of breast cancer in young versus elderly women.

> **NIH NIH U01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $125,909

## Abstract

Aging and obesity are two major risk factors of developing breast cancer. Further, the vast majority of breast
cancers in post-menopausal women are estrogen receptor positive alpha (ERα The reason why aging favors
the development of ERα breast cancer is not known. The overall hypothesis of this application is that
mitochondrial biology plays a fundamental role in these observations. Our group focuses on the mitochondrial
unfolded protein response (UPRmt). We have identified two parallel axes of mitochondria to nucleus
communication in breast cancer. One axis is regulated by the mitochondrial sirtuin SIRT3, a gene tightly linked
to aging. The other is regulated by the ERα. Our overall understanding of the UPRmt is that it acts as a
housekeeping function to ensure mitochondrial repair and fitness in face of elevated ROS found in cancer
cells, allowing the mitochondria to maintain its integrity and generate the metabolites necessary for amino
acids, lipids and nucleotides synthesis; the building blocks of increased cellular mass, characteristic of tumor
growth. We have characterized the UPRmt in breast cancer cells lines and in the inducible ErbB2 mouse model
of breast cancer in vivo. More recently, we took advantage of this mouse model to induce the ErbB2 oncogene
in young and old mice. We found that despite sharing the same oncogene, tumors are significantly larger in old
mice. Further, we perform RNAseq analysis and found genetic signatures that distinguish both groups.
Notably, tumors derived from old mice show decrease in SIRT3 but up-regulation of ER and AKT. Based on
these findings, we hypothesize that as SIRT3 is reduced in older women, upon oncogene activation and ROS
production, ERα cells activate the ERα axis of the UPRmt to survive oxidative stress, therefore providing a
selective advantage for the proliferation of ERα cells. As calorie restriction (CR) is known to increase the
expression for SIRT3, CR is predicted to affect the UPRmt. To further explore these hypotheses, we propose:
Specific aim 1: Characterize what distinguish the genomic profiles of mammary tumors derived from young
versus old females.
Specific aims 2: Test whether calorie restriction affects the genomic profiles of mammary tumors from young
to old and vice versa.

## Key facts

- **NIH application ID:** 9927550
- **Project number:** 5U01AG066098-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** DORIS A GERMAIN
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $125,909
- **Award type:** 5
- **Project period:** 2019-05-15 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9927550

## Citation

> US National Institutes of Health, RePORTER application 9927550, The role of the mitochondrial unfolded protein response (UPRmt) in the etiology of breast cancer in young versus elderly women. (5U01AG066098-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9927550. Licensed CC0.

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