The transport of molecules into and out of the cell is one of the most critical functions of living organisms. A large reason for the failure of chemotherapy in many cases is drug resistance. Pumps that remove toxins from cells are critically important in the resistance of tumors. In addition a number of genetic diseases are caused by defects in transport proteins. The ATP-binding cassette (ABC) gene family codes for transporter proteins pumping a variety of compounds across the membranes of cells and tissues. Overexpression of ABC transporters is an important cause of multidrug resistance to chemotherapy agents and these genes are mutated in diverse human diseases. ABC genes in cancer stem cells Several ABC genes are expressed in cancer stem cells allowing for an innate resistance to cancer therapy. ABCG2 is an important drug resistance gene and we have screened for and identified new inhibitors to the protein encoded by this gene. One of these is a new class of compounds known as botrylamides. The botrylamides are found in marine sponges and are simple enough chemically that derivatives can be synthesized and a structure/function relationship determined. ABCG2 is an important marker and resistance factor in cancer stem cells. Several of these compounds can be shown to inhibit substrate binding and/or ATPase activity of the protein. The ABCB5 gene, that we identified over 10 years ago has been shown to be a marker for melanoma stem cells. We are developing antibodies against this protein and are expressing the protein in culture to further study its function. Metabolomics to study ABC gene Function To understand the function of the ABCC6 gene causing pseudoxanthoma elasticum we have initiated a metabolomics study. Urine from male patients has been used to generate metabolite profiles. We have also initiated studies of serum and urine from Abcc6 -/- mice and from yeast cell deficient in an ABCC subfamily gene. These studies should aid us in identifying the substrate of this transporter. The complete complement of ABC genes was characterized in the sea urchin, a major model organism for development and cell biology. Animal models We find that the sea urchin has a dramatically expanded complement of drug transporter genes as well as orthologs of many human disease genes. In addition we have characterized the complement of ABC genes in the planktic crustacean Daphnia a globally distributed organism of central importance for the ecology of lakes and ponds. Daphnia is not only the first crustacean, but also the first non-insect arthropod to have its genome sequence determined.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005725-16
Application #
7732898
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2008
Total Cost
$772,224
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Idelman, Gila; Jacobson, Eric M; Tuttle, Traci R et al. (2011) Lactogens and estrogens in breast cancer chemoresistance. Expert Rev Endocrinol Metab 6:411-422
Borcherding, Dana C; Hugo, Eric R; Idelman, Gila et al. (2011) Dopamine receptors in human adipocytes: expression and functions. PLoS One 6:e25537
LaPensee, Elizabeth W; LaPensee, Christopher R; Fox, Sejal et al. (2010) Bisphenol A and estradiol are equipotent in antagonizing cisplatin-induced cytotoxicity in breast cancer cells. Cancer Lett 290:167-73
Jacobson, Eric M; Hugo, Eric R; Tuttle, Traci R et al. (2010) Unexploited therapies in breast and prostate cancer: blockade of the prolactin receptor. Trends Endocrinol Metab 21:691-8
Lapensee, Elizabeth W; Tuttle, Traci R; Fox, Sejal R et al. (2009) Bisphenol A at low nanomolar doses confers chemoresistance in estrogen receptor-alpha-positive and -negative breast cancer cells. Environ Health Perspect 117:175-80
Dean, Michael (2009) ABC transporters, drug resistance, and cancer stem cells. J Mammary Gland Biol Neoplasia 14:3-9
Ben-Jonathan, Nira; Hugo, Eric R; Brandebourg, Terry D (2009) Effects of bisphenol A on adipokine release from human adipose tissue: Implications for the metabolic syndrome. Mol Cell Endocrinol 304:49-54
Sturm, Armin; Cunningham, Phil; Dean, Michael (2009) The ABC transporter gene family of Daphnia pulex. BMC Genomics 10:170
Henrich, Curtis J; Robey, Robert W; Bokesch, Heidi R et al. (2007) New inhibitors of ABCG2 identified by high-throughput screening. Mol Cancer Ther 6:3271-8
Lou, H; Dean, M (2007) Targeted therapy for cancer stem cells: the patched pathway and ABC transporters. Oncogene 26:1357-60

Showing the most recent 10 out of 41 publications