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

Knut M. Wittkowski, Christina Dadurian, Martin P. Seybold, Han Sang Kim, Ayuko Hoshino, David Lyden

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12 Citations (Scopus)

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.

Original languageEnglish
Article numbere0199012
JournalPloS one
Volume13
Issue number7
DOIs
Publication statusPublished - 2018 Jul

Bibliographical note

Funding Information:
This work was supported in part by grant # UL1 TR000043 from the National Center for Advancing Transla-tional Sciences (NCATS, National Institutes of Health [NIH], https://www. nih.gov/) Clinical Translational Sci-ence Award (CTSA) program (KMW). The authors gratefully acknowledge support from the following funding sources: The James Paduano Foundation, Nancy C. and Daniel P. Paduano Foundation, Children’s Cancer and Blood Foundation, and 5th District AHEPA Cancer Research Foundation (https:// 5thdistrictahepa-crf.org/, all to DL), Susan G. Komen Postdoctoral Fellowship (http://www. komen.org/, AH), and Physician-Scientist Program from the Yonsei University College of Medicine (http://medicine.yonsei.ac.kr/en/, HSK). The Breast and Prostate Can-cer Cohort Consortium (BPC3) genome-wide association studies of advanced prostate cancer and estrogen-receptor negative breast cancer was supported by the National Cancer Institute (www.cancer.gov) under cooperative agreements U01-CA98233, U01-CA98710, U01-CA98216, and U01-CA98758 and the Intramural Research Program of the National Cancer Institute, Division of Cancer Epidemiology and Genetics. The fun-ders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2018 Wittkowski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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