Complex polymorphisms in endocytosis genes suggest alpha-cyclodextrin as a treatment for breast cancer

Abstract

Most breast cancer deaths are caused by metastasis and treatment options beyond radiation and cytotoxic drugs, which have severe side effects, and hormonal treatments, which are or become ineffective for many patients, are urgently needed. This study reanalyzed existing data from three genome-wide association studies (GWAS) using a novel computational biostatistics approach (muGWAS), which had been validated in studies of 600-2000 subjects in epilepsy and autism. 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. Results from three independent GWAS of 1000-2000 subjects each, which were made available under the National Institute of Health's "Up For A Challenge" (U4C) project, not only confirmed cell-cycle control and receptor/AKT signaling, but, for the first time in breast cancer GWAS, also consistently identified many genes involved in endo-/exocytosis (EEC), most of which had already been observed in functional and expression studies of breast cancer. In particular, the findings include 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 alphacyclodextrins (αCD) as a novel intervention to control local spread of cancer, packaging of exosomes (which prepare distant microenvironment for organ-specific metastases), and endocytosis of β1 integrins (which are required for spread of metastatic phenotype and mesenchymal migration of tumor cells). Beta-cyclodextrins (βCD) have already been shown to be effective in in vitro and animal studies of breast cancer, but exhibits cholesterol-related ototoxicity. The smaller αCDs also scavenges phospholipids, but cannot fit cholesterol. An in-vitro study presented here confirms hydroxypropyl (HP)-αCD to be twice as effective as HPβCD against migration of human cells of both receptor negative and estrogen-receptor positive breast cancer. If the previous successful animal studies with βCDs are replicated with the safer and more effective αCDs, clinical trials of adjuvant treatment with αCDs are warranted in women with triplenegative breast cancer, who progress fast and have few treatment options.peer-reviewed)

Reciprocal priming between receptor tyrosine kinases at recycling endosomes orchestrates cellular signalling outputs

“…FGF10-induced cell cycle progression depends on EGFR_T693 phosphorylation. COSMIC database (Tate et al, 2019) and the importance of trafficking proteins in breast cancer is emerging (Wittkowski et al, 2018).…”

“…Targeting pan RTK trafficking (Porebska et␣al, 2018) and trafficking players, like TTP, RCP, and those identified by TPAs might open up novel therapeutic scenarios for treatment. Indeed, most of the recycling players identified here are mutated in breast cancer according to the COSMIC database (Tate et␣al, 2019) and the importance of trafficking proteins in breast cancer is emerging (Wittkowski et␣al, 2018).…”

“…Importantly, reciprocal priming of RTKs may have implications when only one receptor is targeted as part of personalized therapies, where knock on effects to other pathways are not explored until resistance mechanisms have arisen (Tan et al, 2017). Targeting pan RTK trafficking (Porebska et al, 2018) COSMIC database (Tate et al, 2019) and the importance of trafficking proteins in breast cancer is emerging (Wittkowski et al, 2018).…”

Reciprocal Priming between Receptor Tyrosine Kinases at Recycling Endosomes Orchestrates Cellular Signalling Outputs

“…Targeting pan RTK trafficking (Porebska et al, 2018) and trafficking players, like TTP, RCP, and those identified by TPAs might open up novel therapeutic scenarios for treatment. Indeed, most of the recycling players identified here are mutated in breast cancer according to the COSMIC database (Tate et al, 2019) and the importance of trafficking proteins in breast cancer is emerging (Wittkowski et al, 2018).…”

“…Targeting pan RTK trafficking(Porebska et al, 2018) and trafficking players, like TTP, RCP, and those identified by TPAs might open up novel therapeutic scenarios for treatment. Indeed, most of the recycling players identified here are mutated in BC according to the COSMIC database(Tate et al, 2019) and the importance of trafficking proteins in BC is emerging(Wittkowski et al, 2018).Understanding the extent of RTK regulation "in the right place at the right time" (Barrow-McGee & Kermorgant, 2014) is key for the integration of early signaling and long-term responses in cancer cells. Here, we unveiled a new form of RTK communication, a reciprocal priming within the RE.…”