Doctors would like to diagnose malignancies rapidly by matching them with highly-specific genetic “mug shots” based on the presence of characteristic mRNAs or proteins. This kind of specificity would facilitate screening and early detection, and would potentially allow targeted treatments specific to each type of cancer.
Painstakingly detailed research is required to find and confirm such ‘mug shots,’ but is worth the effort as seen in recent studies of an ATP-binding cassette (ABC) transporter protein, named ABCB5, in human melanoma cells. Kevin G. Chen, a research fellow in Michael M. Gottesman’s laboratory at the National Institutes of Health (NIH), reports the first systematic demonstration that normal skin pigment-forming cells (melanocytes) and cancerous melanoma cells express different isoforms of the ABCB5 transporter via alternative mRNA splicing.
ABC transporters are membrane-spanning proteins that export a variety of molecules across cell membranes. Powered by ATP hydrolysis, the 48 different ABC transporters encoded by the human genome play pivotal roles in normal physiology. In melanomas, aberrant ABCB5 transporters may allow cells to resist chemotherapy, even when multiple drugs are used. Chen and colleagues found mRNAs corresponding to two novel isoforms of ABCB5, named ABCB5a and ABCB5b, that were preferentially expressed in 75 percent of the melanomas represented in the National Cancer Institute-60 (NCI-60) panel of cancer cell lines. The first isoform, ABCB5a, comprises only a partial ABC transporter and is probably not functional alone. The other isoform, ABCB5b, is approximately 70 percent similar to the protein encoded by a different gene, ABCB1 (a.k.a. MultiDrug Resistance gene, MDR1), and has a predicted membrane topology similar to the carboxyl terminal half of ABCB1. Neither ‘aberrant’ isoform was expressed in normal tissues from the liver, spleen, thymus, kidney, heart, lung, colon, small intestines or placenta. However, they are the predominant ABCB5 isoforms expressed in melanoma cells, normal melanocytes and pigment-forming retinal cells, suggesting that ABCB5a/b expression is limited to cells that normally produce pigment.
How would these special versions of ABCB5 lead to multi-drug resistance in melanomas? Chen and Gottesman speculate that normal ABCB5 transporters help cells export cytotoxic compounds currently used as anti-cancer drugs. One or both of the aberrant ABCB5 isoforms are proposed to work in conjunction with other isoforms to enhance drug export and make melanoma cells drug-resistant. Supporting this model, cells that express the ABCB5b isoform have a drug response pattern different from that of ABCB1-expressing cells. These ideas will be tested further. Meanwhile, the discovery that ABCB5a/b isoforms ‘mark’ most cancerous melanomas provides two molecular markers for the differential diagnosis of melanomas, and might be used to specifically target melanomas in anti-cancer therapy.