Date Published: July 2, 2018
Publisher: Public Library of Science
Author(s): Knut M. Wittkowski, Christina Dadurian, Martin P. Seybold, Han Sang Kim, Ayuko Hoshino, David Lyden, Aamir Ahmad.
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.
Breast cancer is the most common cancer in women worldwide. In 2016, 246,660 new U.S. cases were estimated. 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. Patients with breast cancer positive for estrogen receptor (ER) or human epidermal growth factor (GF) receptor type 2 (HER2) initially respond well to anti-estrogen or anti-HER2 therapy, respectively, but inevitably become refractory.
Our analysis confirmed previous GWAS, which pointed to receptor/AKT signaling and nuclear functions as critical components in breast cancer etiology. The present results from a reanalysis of data found previously inconclusive provides the first GWAS evidence for the contribution of EEC dysfunction and novel evidence for overstimulation of EEC in mesenchymal tumor cell migration and invasion. These findings, confirmed by an in vitro study on the activity of HPαCD vs HPβCD against breast cancer cell migration, suggest the novel hypothesis that reducing the influx of phospholipids, including PS, PC, and lysophosphatidylcholine (LPC), into the PI cycle via HPαCD could provide an urgently needed treatment option for women with breast cancer.