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Abstract Hypoxia is an important hallmark of aggressive solid tumors and a key driver of metastasis and resistance to therapy. Hypoxic stress induces the activation of various factors, such as hypoxia- inducible factors (HIFs), which facilitate cellular adaptation and promote tumorigenesis. Given the complexity of this mechanism, identifying novel targets that sensitize hypoxic tumors to therapy could have significant clinical impact. We demonstrate HIF-independent induction of BACH1 within multiple TNBC (Triple-Negative Breast Cancer) cell lines and patient-derived organoids under hypoxic conditions. Utilizing ChIP-seq, bulk, single-cell and spatial transcriptomics across diverse BACH1 knockout tumor models, our study revealed that BACH1 selectively and directly modulates the transcriptional response associated with hypoxia and stress in TNBC. TGCA analysis reveals racial disparities in BACH1 mRNA expression in TNBC BACH1 mRNA and activity 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, Madeline Henn, Emily Shi, Thomas Li, Kent Schechter, Letícia Stock, Wenchao Liu, Margarite Matossian, Andrea Valdespino, Yoo Jane Han, Jing Zhang, Geetha Priyanka Yerradoddi, Yan Li, Mitsuyo Matsumoto, Olufunmilayo I Olopade, Kazuhiko Igarashi, Marsha R Rosner. Racial differences in expression of the oxygen-sensor BACH1 in breast cancer abstract. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C121.
Nguyen et al. (Sat,) studied this question.