Heat shock proteins as a promising breast cancer therapeutic

Heat shock protein 90, or Hsp90, is a ubiquitously expressed molecular chaperone. It serves as a promising target for the development of anticancer therapeutics due to its role in regulating multiple oncoproteins. An expansive variety of small-molecule Hsp90 pan-inhibitors have previously gone to trial, but many have failed due to cardiotoxicity and ocular toxicity attributed to Hsp90α, one of two cytosolic isoforms of the protein. This has ultimately led to the development of isoform-specific therapeutic strategies using Hsp90.

Ewa Krawczyk, National Cancer Institute, National Institutes of Health, via NIH Flickr

Image shows a cell culture of human breast cancer conditionally reprogrammed cells. Red represents MHC-I, and nuclei are shown in blue.

Tyelor Reynolds and colleagues at the University of Notre Dame recently sought to identify the anticancer effects of Hsp90β-selective inhibitors and how this may affect the proteome. The study was published in Molecular & Cellular Proteomics. They used a bottom-up liquid chromatography–mass spectrometry/mass spectrometry, or LC–MS/MS, proteomics approach to perform the first proteomic analysis of Hsp90β-selective inhibitors NDNB1 and NDNB1182 against triple-negative breast cancer, or TNBC. The study determined that both NDNB1 and NDNB1182 display moderate selectivity for TNBC cells, and inhibition of Hsp90β using these inhibitors led to alterations in proteins associated with cell cycle functions, cell signaling pathways and DNA repair mechanisms.

The researchers also identified additional potential Hsp90β substrates, including RAD9 checkpoint component A, or RAD9A, a cell cycle checkpoint protein involved in DNA repair; cyclin-dependent kinase 1, or CDK1, a key regulator of the cell cycle; and ribosomal protein S9, or RPS9, which contributes to ribosomal subunit formation. These discoveries provide insights into Hsp90 isoforms and their potential as anticancer therapeutics.