Abstract PS5-03-22: Lactate driven upregulation of BACH1 promotes metastatic dissemination in triple negative breast cancer

Abstract Patients with triple negative breast cancer (TNBC) experience the highest mortality and lowest metastasis-free survival rate amongst all other breast cancer subtypes. TNBC is characterized by absence of hormone receptors; estrogen receptor and progesterone receptor, and HER2 receptor, which limits the effectiveness of targeted therapies, highlighting the need for further study. One key factor, BTB and CNC homology 1 (BACH1), a heme-binding transcription factor, is upregulated in TNBC compared to other breast cancer subtypes. Previous studies have identified BACH1 as a regulator of metastasis in cancers, including TNBC. While much of the focus has been on the intrinsic regulation of BACH1, the impact of the tumor microenvironment (TME), specifically nutrients like lactate, on BACH1 regulation and TNBC metastasis is unknown. Cancer cells rely on heightened glycolysis, leading to excessive lactate production, even in the presence of oxygen. This metabolic shift supports both tumor growth and metastasis. Given the emerging role of lactate as a key signaling molecule, we explored how lactate in the TME directly regulates BACH1 expression and contributes to metastasis of TNBC. In vitro simulation of a lactate rich microenvironment using human and murine TNBC cell lines resulted in increased BACH1 protein expression while mRNA expression remained unregulated. Additionally, lactate accumulation in the microenvironment led to BACH1-dependent increase in invasion and migration of TNBC, while proliferation remained unregulated. To understand the mechanism of lactate mediated upregulation of BACH1, a recently identified posttranslational modification, lysine lactylation (Kla) was investigated utilizing global lactylation analysis and BACH1 specific interactome under lactate rich conditions. These findings represent a novel regulatory mechanism by which lactate in tumor microenvironment contributes to metastasis of TNBC through lactylating BACH1 or its interacting partners. These results suggest that targeting BACH1 stability through lactylation inhibition could serve as a promising approach to limit TNBC metastatic progression, especially in aggressive, therapy-resistant cases. Citation Format: J. Padilla, Y. Park, A. Bansal, A. Banduru, J. Lee. Lactate driven upregulation of BACH1 promotes metastatic dissemination in triple negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-03-22.