Abstract
Abstract Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, is more prevalent among African American and underserved female populations. Hypoxia has recently been identified as one of the main drivers of TNBC, particularly within the African American cohort. Therefore, it is important to identify and target key regulators of hypoxia. Here we show that the pro-metastatic transcription factor BACH1 is induced by hypoxia and regulates the hypoxia response in TNBC tumor cells. BACH1 protein is destabilized via an oxygen-dependent prolyl-hydroxylation pathway, akin to Hypoxia-inducible Factors (HIFs). BACH1 mutants (BACH1M) resistant to hydroxylation exhibit heightened transcriptional activity and metastatic potential both in vitro and in vivo. TGCA analysis reveals that TNBC exhibits elevated BACH1 mRNA and hypoxia signature, irrespective of racial ancestry. Nevertheless, racial disparities in BACH1 mRNA expression exist across all breast cancer subtypes (Basal, Her, LumA, LumB). Our findings suggest that BACH1 is an oxygen-sensitive mediator of hypoxia and a promising therapeutic target for mitigating hypoxia-induced pro-metastatic signaling and treatment resistance. These results also highlight the necessity of accounting for racial differences in BACH1 expression and function as a means of developing targeted therapy that takes into account racial disparities in TNBC. Citation Format: Long C. Nguyen, Christopher Dann, Dongbo Yang, Emily Shi, Thomas Li, Leticia Stock, Madeline Henn, Galina Khramtsova, Wenchao Liu, Mitsuyo Matsumoto, Olufunmilayo Olopade, Kazuhiko Igarashi, Marsha Rosner. BACH1 regulates the hypoxia response and metastasis in triple negative breast cancer [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C070.
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