# Understanding lactate catabolism by BACH1 in triple negative breast cancer

> **NIH NIH R37** · GEORGE WASHINGTON UNIVERSITY · 2022 · $484,884

## Abstract

PROJECT SUMMARY
 Primary metabolic pathways in cancer are useful targets for therapeutic intervention. However, intratumoral
heterogeneity in cancer metabolism is a major challenge for anti-cancer therapy. Reducing metabolic variance
by reprogramming cancer metabolism is essential to enhance efficacy of inhibitors targeting metabolism. Our
long-term goal is to overcome metabolic heterogeneity through reprogramming metabolic networks to increase
the number of cancer cells vulnerable to metabolic inhibitors. To reach this goal, our novel strategy is to reduce
metabolic variance among cancer cells by targeting BACH1, a master regulator of metabolism-related
transcription in triple negative breast cancer (TNBC), to obtain maximal response of drugs targeting metabolic
pathways. Our previous molecular and metabolomic profiling of breast tumors revealed that BACH1 suppresses
mitochondrial metabolism. Thus, BACH1 depletion made TNBC cells more sensitive to mitochondrial inhibitors.
These findings led to the novel concept that BACH1 depletion increases the proportion of cancer cells with higher
dependency on mitochondrial respiration and restricted tumor metabolic plasticity. Our preliminary studies
indicate that BACH1 also suppresses lactate catabolism, which is a primary pathway for lactate oxidation in
mitochondria of cancer cells. In support of this finding, recent clinical studies showed that lactate catabolism
depends on lactate transporter (MCT1). In TNBC cells, BACH1 represses transcription of genes that encode
enzymes involved in lactate catabolism, including lactate transporter (MCT1), lactate dehydrogenase B (LDHB),
and mitochondrial pyruvate carriers. Specifically, BACH1 depletion sensitized cancer cells to blockade of MCT1
or LDHB. Based on our preliminary data, we hypothesize that BACH1 is the key determinant of whether cancer
cells produce lactate or consume lactate. The primary objective of this proposed study is to link BACH1
contribution to lactate catabolic variance, and to better understand regulation of lactate oxidation in TNBC. Using
multiple innovative approaches, including in vitro and in vivo breast tumor models and a combination of
transcriptomics and metabolomics, we will interrogate BACH1 regulation of lactate catabolism and define the
underlying molecular regulatory mechanism in breast cancer cells. Furthermore, using patient-derived xenograft
and syngeneic mouse models, we will investigate whether BACH1 inhibition (through the repurposed non-toxic
FDA-approved drug, panhematin) increases breast tumor vulnerability to drugs targeting the lactate transporter
MCT1. By combining cell biology and in vivo assays, this study will provide comprehensive insights into how
cancer cells use lactate as a substrate, whether metabolic variances are reduced by targeting BACH1, and how
to achieve better therapeutic strategies using lactate catabolism inhibitors.

## Key facts

- **NIH application ID:** 10423494
- **Project number:** 1R37CA270536-01
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Jiyoung Lee
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $484,884
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10423494

## Citation

> US National Institutes of Health, RePORTER application 10423494, Understanding lactate catabolism by BACH1 in triple negative breast cancer (1R37CA270536-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10423494. Licensed CC0.

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