CMET-19. THE ROLE OF BRAIN SPECIFIC FATTY ACID BINDING PROTEIN 7 IN BREAST CANCER METASTASES TO THE BRAIN

Abstract

HER2 overexpression in breast cancer increases the incidence of brain metastasis. Brain metastases are established after extravasation of cancer cells in the glia followed by invasion in the brain microenvironment. To identify critical genes for establishment of brain metastases, we conducted an In silico screening of publicly available datasets. Our screening identified FABP7 to be significantly overexpressed in brain metastatic patients as compared to patients with systemic metastases. In the NKI dataset overexpression of FABP7 was also correlated with poor prognosis. FABP7 is a brain-specific gene responsible for brain development and lipid metabolism. To establish the role of FABP7 in the brain metastatic process, FABP7 shRNA knockdown studies were conducted in BT-474BrM3 cells. Our results demonstrated a reduction in invasion ability of FABP7 knockdown cells. This result was accompanied with a significant decreased expression of genes that play a key role in the metastatic process such as OCT4, NANOG, ZEB2 or Carbonic anhydrase IX (Ca9). Moreover, phosphorylation of the p38 MAPK and ATF-2, another key signaling pathway regulating metastasis, was abrogated by FABP7 knockdown, suggesting that FABP7 is required for the kinase activity of p38 MAPK. In lieu of the fact that brain is normally under hypoxic environment, we simulated hypoxia in cell culture models. Interestingly under hypoxic conditions, FABP7 knockdown cells failed to induce angiogenic and invasive markers, such as VEGFA or PTPRZ1. Altogether, our results indicate that the expression of FABP7 by brain metastatic breast cancer cells allows the breast cancer cells to invade within the central nervous system.