# Targeting Serine Auxotrophy in Luminal Breast Cancer

> **NIH NIH R37** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $341,706

## Abstract

PROJECT SUMMARY/ABSTRACT
 A major challenge of targeting metabolism for cancer therapy is pathway redundancy, where multiple
sources of critical nutrients can diminish the effects of metabolic therapies. An example of this can be found in
recent attempts to target the serine synthesis pathway for cancer therapy, where the abundance of serine
available to be taken up from the circulation has hampered the success of inhibitors of serine biosynthesis. This
places a premium on pursuing strategies of limiting pathway redundancy if we wish to successfully target serine
and other critical metabolic pathways for cancer therapy. We have taken the approach of analyzing human tumor
gene expression data to identify scenarios where pathway redundancy is limited due to lineage-dependent gene
expression, thereby creating potential vulnerabilities. Using this approach, we have found that the two major
lineages of breast tumors—luminal and basal—express vastly different levels of PSAT1 (phosphoserine
aminotransferase 1), the gene encoding the second enzyme of the serine synthesis pathway. Luminal breast
cancer cells, which express extremely low levels of PSAT1, are unable to activate the serine synthesis pathway
even when extracellular serine is completely absent. As a result, they are entirely dependent on exogenous
serine for proliferation and survival. This is in contrast to basal breast cancer cells, which are able to synthesize
serine and proliferate in the absence of extracellular serine. Mechanistically, this serine auxotrophy appears to
be due to luminal-specific methylation of the PSAT1 gene. Based on this data, we have developed the hypothesis
that lineage-specific epigenetic silencing of the PSAT1 gene induces serine auxotrophy in luminal breast tumors
and makes them vulnerable to inhibition of serine uptake. In this proposal, we will 1) determine whether luminal
breast tumors are sensitive to dietary serine starvation in vivo, 2) define the mechanism of PSAT1 suppression
in luminal tumors, and 3) identify and characterize serine transporters as potential pharmacological targets of
this vulnerability. While luminal breast cancer patients initially have a favorable prognosis due to the utility of
endocrine therapies, over half of all patients eventually develop resistance to these therapies and undergo
relapse. As a result, over half of all breast cancer fatalities are due to luminal breast cancer, making this an area
of significant unmet clinical need. The experiments described in this proposal have the potential to identify new
therapeutic options for patients with advanced luminal breast cancer.

## Key facts

- **NIH application ID:** 10794286
- **Project number:** 5R37CA251216-04
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Jonathan L. Coloff
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $341,706
- **Award type:** 5
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10794286

## Citation

> US National Institutes of Health, RePORTER application 10794286, Targeting Serine Auxotrophy in Luminal Breast Cancer (5R37CA251216-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10794286. Licensed CC0.

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