Impact of heme catabolism on triple negative breast cancer metastasis via immune-suppression

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Abstract/Project Summary Triple negative breast cancer (TNBC) has more frequent and rapid metastasis than other breast cancer (BC) subtypes and >20% of patients progress on standard of care therapies within 5 years of diagnosis. Increased early invasiveness could be a result of epithelial to mesenchymal transition (EMT), which many TNBCs have partially undergone to increase cell motility, induce chemotherapy resistance, and promote immune evasion. Reversal of EMT using the micro-RNA miR-200c revealed several immune-suppressive catabolizing enzymes that are increased in mesenchymal-like BCs when compared to more epithelial counterparts, such as HMOX1 (heme oxygenase-1, HO-1). Interestingly, HO-1 is expressed in many cell types in the tumor microenvironment and previous studies show that targeting HO-1 in immune cells can limit tumor progression in preclinical models. However, there is a gap in knowledge regarding the role of breast tumor cell- HO-1 and its catabolites in metastasis, chemotherapy resistance, and immune evasion. My preliminary data showed that HO-1 expression was increased in lung metastases from two TNBC-like mammary tumor models when compared to their respective primary tumors. In an additional spontaneous metastasis model, HO-1 expression was also increased in lung metastases. Previous studies and my preliminary results also show that chemotherapy induces HO-1 expression. Given the important role HO-1 may have in breast tumor progression, it is critical to further investigate HO-1 in TNBC cells during metastasis and chemotherapy resistance, which I will study in Aim 1. HO-1 targeting with a clinically approved HO inhibitor will also be explored and compared to tumor cell specific HO-1 inhibition (shRNA) in clinically relevant, immune- competent TNBC-like mouse models. HO-1 degrades heme to produce catabolites that suppress normal immune cell function in a paracrine manner. One such catabolite bilirubin (BR) has powerful immune-suppressive roles in other diseases, but has not been explored in cancers as an immunosuppressant. My preliminary data further demonstrate that BR is immune-modulatory and showed that BR treatment altered the function of macrophages by limiting expression of M1 polarization genes and by halting efferocytosis, macrophage engulfment of dead cells. Previous studies show that serum BR levels increase after chemotherapy treatment in BC patients. Therefore, it is essential to understand whether elevated HO-1 expression during breast tumor progression can enhance tumor-derived bilirubin that in turn limits immune cell function. This idea will be assessed in Aim 2 where I will study the impact of bilirubin on tumor immune-suppression. Together, the aims proposed herein will determine if HO-1 is a novel clinical target to limit metastasis and reactivate the anti-tumor immune response in a non-contact dependent manner. These studies could reveal new treatment strategies with the potential to enhance the efficacy of current TNBC therapies such as chemotherapy and checkpoint blockade.