The ABCs and HSPs of Breast Cancer: Researchers Target MDR and Stress Proteins to Reverse Chemoresistance and Cardiotoxicity

ATP-binding cassette (ABC) transporters belong to a highly conserved superfamily of transmembrane proteins involved in the efflux of a variety of substrates, including chemotherapeutic drugs such as doxorubicin, out of the cell. Expression of the transporters P-glycoprotein (MDR1, ABCB1), MRP1 (ABCC1) and BCRP (ABCG2) is up-regulated in a majority of cancers, a phenomenon linked to the accumulation of mutant p53 and its atypical transcriptional activity in cooperation with NFkB. Although an effective antineoplastic, doxorubicin has unwanted side effects, particularly cardiotoxicity that can lead to congestive heart failure.

In two recent publications in The Journal of Biological Chemistry, and The Proceedings of the National Academy of Sciences, Dr. Govindasamy Ilangovan of The Ohio State University and colleagues shed light on the role of the small heat shock protein HSP27 and the stress-inducible transcription factor HSF-1 in these two unwanted outcomes. In the first, the authors demonstrate that forced expression of HSP27 in a doxorubicin-resistant MCF-7 breast cancer cell line significantly reduced mutant p53 and NFκB levels, and mediated repressed expression of P-glycoprotein. The net effect was decreased drug efflux and increased apoptosis, demonstrating the potential therapeutic benefit of modulating HSP27 expression in tumor cells to reduce chemoresistance.

In the second, the authors describe an interesting twist: increasing P-glycoprotein expression in cardiomyocytes via inhibition of HSF-1/NFκB transactivation appears to be part of a protective mechanism that could abrogate doxorubicin associated cardiotoxicity. Gene-based or pharmacological therapies targeting HSF-1 expression in the heart could enhance the effectiveness of such anti-cancer drugs by reducing their cardiotoxic side effects.

Enzo Life Sciences offers a comprehensive portfolio for studying the role of multidrug resistance and cell stress proteins in cancer, including live cell analysis kits, transporter-specific dyes, antibodies, and biochemicals (inhibitors and activators), some of which are briefly described below.

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