Kalita-de Croft, P. | bioRxiv Science

bioRxiv2020

Immunophenotyping of HER4/YAP axis in breast cancer brain metastasis

Brain metastasis (BrM) is a devastating diagnosis for patients with breast cancer. Identification of immunophenotypical features specific to BrM is crucial for developing effective new therapeutic interventions. Yes-associated protein (YAP) mediates downstream effects of the neuregulin receptor, HER4, on breast cancer cell proliferation in vitro. HER4 is frequently over-expressed in BrM, but the relationship with YAP has not been investigated. This study examined the HER4/YAP axis in patient samples (n=41) from matched primary breast and metastatic brain tumours. Immunohistochemistry analysis revealed HER4 was highly phosphorylated in BrM compared to matched primary tumours (p=0.0022), and this was strongly associated with expression and phosphorylation of dimerization partners HER2 and HER3 (p<0.0001). When compared to a general breast cancer cohort (n=373), we found HER4 activation to be brain metastasis specific (p<0.0001). However, YAP was frequently phosphorylated in both HER4-activated primary breast tumours and brain metastases, suggesting that pro-proliferative YAP signaling is not a major consequence of HER4 activation in these tumours. These results display the complexity of expression of the HER family receptors and the downstream pathways in BrM and suggest simultaneous targeting of multiple receptors might be more advantageous.

pathology↗

bioRxiv2019

Marizomib suppresses triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition

Lacking effective targeted therapies, triple-negative breast cancer (TNBCs) is highly aggressive with development of metastasis especially brain, and remains clinically challenging breast cancer subtype to treat. Despite the survival dependency on the proteasome pathway genes, FDA-approved proteasome inhibitors induced minimal clinical response in breast cancer patients due to weak proteasome inhibition. Here, we show that a potent proteasome inhibitor Marizomib (Mzb) inhibits multiple proteasome catalytic activities and induces a better anti-tumor response in TNBC cell lines and patient-derived xenografts alone and in combination with the standard-of-care chemotherapy. Mechanistically, Mzb inhibits oxidative phosphorylation (OXPHOS) via PGC-1 suppression in conjunction with proteasome inhibition in TNBC cells. Mzb reduces lung and brain metastases by reducing the number of circulating tumor cells and the expression of multiple genes involved in the epithelial-to-mesenchymal transition. Furthermore, Mzb-induced OXPHOS inhibition upregulates glycolysis to meet the energetic demands of TNBC cells and, hence, combined inhibition of glycolysis with Mzb exposure leads to a synergistic anti-cancer activity. Collectively, our data provide a strong rationale for a clinical evaluation of Mzb in primary and metastatic TNBC patients.\n\nOne Sentence SummaryMarizomib inhibits primary tumor growth, and also reduces lung and brain metastases in pre-clinical models of triple-negative breast cancer.

cancer biology↗