Complex polymorphisms in endocytosis genes suggest alpha-cyclodextrin against metastases in breast cancer

Most breast cancer (BC) deaths are caused by metastasis and treatment options beyond radiation and cytotoxic drugs are urgently needed. This study reanalyzed existing data from genome-wide association studies (GWAS) using a novel computational biostatistics approach (muGWAS), which had been validated in epilepsy and identified a potential drug against disruption of language development in autism. Compared to many traditional bioinformatics approaches, muGWAS jointly analyzes several neighboring single nucleotide polymorphisms while incorporating knowledge about genetics of heritable diseases into the statistical method and about GWAS into the rules for determining adaptive genome-wide significance in samples of 600-2000 subjects only. Results from three independent breast cancer GWAS not only confirmed cell-cycle control and receptor/AKT signaling, but, for the first time in GWAS, also consistently identified many endo-/exocytosis (EEC) pathway genes, most of which had already been observed in functional and expression studies of breast cancer, including genes that translocate (ATP8A1, ATP8B1, ANO4, ABCA1) and metabolize (AGPAT3, AGPAT4, DGKQ, LPPR1) phospholipids entering the phosphatidylinositol cycle, which controls EEC. These novel findings suggest scavenging phospholipids via alpha-cyclodextrin (aCD) as a potential intervention to control packaging of exosomes (which prepare distant microenvironment for organ-specific metastases) and endocytosis of b1 integrins (which are required for mesenchymal migration of tumor cells). Beta-cyclodextrin (bCD) had already been shown to be effective in vitro and animal studies of breast cancer, but exhibits cholesterol-related ototoxicity. The smaller aCD also scavenges phospholipids, but cannot fit cholesterol. An in-vitro study presented here confirmed hydroxypropyl (HP)-aCD to be at least twice as effective as HPbCD against migration of human cells of both receptor negative and estrogen-receptor positive breast cancer. If the previous successful animal studies with bCDs are replicated with the safer and more effective aCDs, clinical trials of aCDs are warranted in women with triple-negative breast cancer, who have few treatment options and poor prognosis.