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 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 alpha-cyclodextrins (αCD) 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. Ultimately, all breast cancer are expected to benefit from treatment with HPαCD, but women with triple-negative breast cancer (TNBC) will benefit most, because they have fewer treatment options and their cancer advances more aggressively.

Thy-1 (CD90)-Induced Metastatic Cancer Cell Migration and Invasion Are β3 Integrin-Dependent and Involve a Ca2+/P2X7 Receptor Signaling Axis

“…Over the last decades, genome-wide association studies (GWASs) have successfully identified cell adhesion molecules as one of the most prominent group of genes whose expression is altered in melanoma and breast cancer cells ( Akbani et al, 2015 ; Wittkowski et al, 2018 ). Among these genes, integrins stand out because they are the receptors that facilitate adhesion, migration, and invasion of cancer cells.…”

Hydroxypropyl‑β‑cyclodextrin attenuates the epithelial‑to‑mesenchymal transition via endoplasmic reticulum stress in MDA‑MB‑231 breast cancer cells

“…Breast cancer (BC) has a high mortality rate, which is largely due to development of metastases (1). The epithelial-to-mesenchymal transition (EMT) serves a central role in metastasis formation, and is thus an important treatment target (2,3).…”

2-Hydroxypropyl-β-cyclodextrin Regulates the Epithelial to Mesenchymal Transition in Breast Cancer Cells by Modulating Cholesterol Homeostasis and Endoplasmic Reticulum Stress

“…For instance, β-cyclodextrin has been used to treat Niemann-Pick Disease Type C and to promote atherosclerosis regression by releasing trapped cholesterol from lysosomes and normalizing cholesterol levels in the liver [ 21 , 22 , 23 ]. With these properties, HP-β-CD is widely used to deplete cholesterol from cell membranes and lipid rafts, which can affect many signaling pathways [ 24 , 25 ]. Numerous studies have shown that HP-β-CD can inhibit the metastasis of triple-negative breast cancer cells by depleting cholesterol [ 25 , 26 , 27 , 28 ].…”

“…With these properties, HP-β-CD is widely used to deplete cholesterol from cell membranes and lipid rafts, which can affect many signaling pathways [ 24 , 25 ]. Numerous studies have shown that HP-β-CD can inhibit the metastasis of triple-negative breast cancer cells by depleting cholesterol [ 25 , 26 , 27 , 28 ]. In addition, the effect of HP-β-CD on cellular cholesterol has been demonstrated to be closely related to their concentration and the cholesterol content of treated cells [ 29 , 30 ].…”