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.
Highlights
Breast cancer is the most common cancer in women worldwide.[1]
Additional ssGWAS CGEM results complement known breast cancer risk factors The original CGEM analysis had identified two SNPs in the fibroblast growth factor (GF) receptor FGFR2 Entrez Gene 2263,[7] which affects mammary epithelial cell growth and migration,[31] and a SNP which was subsequently located to a long variant of the mitotic checkpoint protein BUB3 9184
After loss-of-function in PTEN and gain-of-function in PI3K suggested a mechanism for upregulation of PI(3,4,5)P3 in cancer, blocking PI3K with Wortmannin [59] or related drugs [60] were considered for treatment of cancers, including breast cancer
Summary
Breast cancer is the most common cancer in women worldwide.[1] In 2016, 246,660 new U.S cases were estimated.[2] The highly penetrant, but rare mutations in BRCA1 and BRCA2 point to DNA repair deficiencies as an etiological factor, but explain only 5 to 10 percent of cases. As of May, 2016, the deadline for participation in the National Cancer Institutes’ “Up For A Challenge” (U4C) breast cancer challenge, 127 single nucleotide polymorphisms (SNPs) had been associated with breast cancer in women of European ancestry [4] at the conventional fixed s = −log(p) = 7.3 level for genome-wide statistical significance (GWS) [5] (s is used throughout for significance). The U4C aimed to generate novel testable biological hypotheses (80 FR 32168)
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