# Mechanisms for the pro-metastatic effects of hyperinsulinemia on breast cancer

> **NIH NIH R56** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $169,000

## Abstract

Abstract
Over the past number of years, we and others have been found that high levels of circulating insulin contribute
to the development and progression of a number of cancers through epidemiology and pre-clinical studies.
Although hyperinsulinemia frequently occurs in individuals with obesity, and early type 2 diabetes, there are also
“metabolically unhealthy” individuals with hyperinsulinemia who are classified as having a normal weight by
traditional definitions. Hyperinsulinemia is therefore a marker of metabolic disease irrespective of body mass,
and as such has been associated with an increased risk of triple negative breast cancer (TNBC). Through our
work to date in this R01, we have found that hyperinsulinemia drives tumor growth directly by activating the
insulin receptor signaling pathway, leading to increased expression of proteins associated with breast cancer
metastasis, such as myc, vimentin and twist. Our pre-clinical results led to another collaborative project where
we investigated the role of hyperinsulinemia in the racial disparities in breast cancer prognosis in self-identified
Black and White US women. By renewing this R01, we aim to gain a greater understanding of the importance of
the insulin receptor (IR) in mediating the effects of insulin in tumor cells, and molecular mechanisms involved.
The IR exists as two isoforms, IR-A and IR-B that differ by one exon. In the setting of systemic metabolic diseases
and cancer, there appears to be an isoform switch where tissues predominantly express IR-A. The isoform
switching is hypothesized to contribute to cancer development and progression. Previous studies have found
that IR-A isoform expression differs in breast cancers from women of different races, potentially making tumors
more susceptible to the growth promoting effects of hyperinsulinemia. Much of our knowledge regarding the
metabolic effects of IR-B and IR-A are based on human correlative studies, and studies of cell lines
overexpressing IR-A or IR-B in vitro. In this research proposal, we will use patient derived xenograft (PDX)
models with a range of IR-A / IR-B ratios to determine if hyperinsulinemia contributes to isoform switching in vivo
using our hyperinsulinemic mice, and also to understand the downstream signaling pathways and gene
expression changes resulting from expression of the different IR isoforms. Through our newly generated mouse
models of tissue specific IR exon 11 deletion, we will examine how tumor cell IR-A expression contributes to
TNBC development and progression. We will also delve into the mechanisms through which insulin receptor
signaling regulates myc regulated genes. Our proposal will provide new insight into mechanisms through which
hyperinsulinemia and IR isoform switching contribute to TNBC development and progression, and the
downstream signaling mechanisms involved in hyperinsulinemia driven breast cancer progression.
Understanding these mechanisms will help us to uncover ways to trea...

## Key facts

- **NIH application ID:** 10522060
- **Project number:** 2R56CA128799-11A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** DEREK LEROITH
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $169,000
- **Award type:** 2
- **Project period:** 2008-04-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522060

## Citation

> US National Institutes of Health, RePORTER application 10522060, Mechanisms for the pro-metastatic effects of hyperinsulinemia on breast cancer (2R56CA128799-11A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10522060. Licensed CC0.

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