The Chaperone System in Breast Cancer: Roles and Therapeutic Prospects of the Molecular Chaperones Hsp27, Hsp60, Hsp70, and Hsp90

Abstract

Breast cancer (BC) is a major public health problem, with key pieces of information needed for developing preventive and curative measures still missing. For example, the participation of the chaperone system (CS) in carcinogenesis and anti-cancer responses is poorly understood, although it can be predicted to be a crucial factor in these mechanisms. The chief components of the CS are the molecular chaperones, and here we discuss four of them, Hsp27, Hsp60, Hsp70, and Hsp90, focusing on their pro-carcinogenic roles in BC and potential for developing anti-BC therapies. These chaperones can be targets of negative chaperonotherapy, namely the elimination/blocking/inhibition of the chaperone(s) functioning in favor of BC, using, for instance, Hsp inhibitors. The chaperones can also be employed in immunotherapy against BC as adjuvants, together with BC antigens. Extracellular vesicles (EVs) in BC diagnosis and management are also briefly discussed, considering their potential as easily accessible carriers of biomarkers and as shippers of anti-cancer agents amenable to manipulation and controlled delivery. The data surveyed from many laboratories reveal that, to enhance the understanding of the role of the CS in BS pathogenesis, one must consider the CS as a physiological system, encompassing diverse members throughout the body and interacting with the ubiquitin–proteasome system, the chaperone-mediated autophagy machinery, and the immune system (IS). An integrated view of the CS, including its functional partners and considering its highly dynamic nature with EVs transporting CS components to reach all the cell compartments in which they are needed, opens as yet unexplored pathways leading to carcinogenesis that are amenable to interference by anti-cancer treatments centered on CS components, such as the molecular chaperones.

Chaperones—A New Class of Potential Therapeutic Targets in Alzheimer’s Disease

“…Chaperones may help diagnose many disorders, for example, tumors [ 94 , 95 ], heart diseases [ 96 ], rheumatologic disorders [ 97 ], and infectious or neurodegenerative disorders [ 98 ]. Hsp70 levels increase as a result of the accumulation of physical and chemical agents or stressors during life.…”

Omics-Based Investigations of Breast Cancer

“…Derived from proteomics, chaperomics investigates the chaperone system, as well as its functional partners and its involvement in carcinogenesis. Many molecular chaperones, such as HSP27, HSP60, HSP70, and HSP90, emphasize a protumorigenic role in BC and have become a valuable target for chaperonotherapy based on the inhibition of pro-cancer chaperones [ 251 ]. In relation to interactomics, in 2022, Ginsberg et al introduced the term epichaperomics to define the link between stressor-induced protein interactome network modifications to the formation of the pathological scaffolds named epichaperomes in Alzheimer’s disease [ 4 ].…”

Hsp70 and Calcitonin Receptor Protein in Extracellular Vesicles from Glioblastoma Multiforme: Biomarkers with Putative Roles in Carcinogenesis and Potential for Differentiating Tumor Types

“…GBM-derived EVs are enriched in immunostimulatory molecules (MHC I/II), cytoskeleton molecules (actin, myosin, and tubulin), membrane-trafficking proteins (Rab GTPases), and heat shock proteins (Hsps), for instance Hsp60, Hsp70, and Hsp90 [ 25 , 26 ]. These Hsps are molecular chaperones whose expression is upregulated following stressful stimuli, such as heat and physical exercise, as well as in pathological conditions [ 27 , 28 , 29 , 30 , 31 , 32 ]. We recently studied the tissue levels of Hsp27, Hsp60, Hsp70, and Hsp90 in GBM samples and GBM cell lines, and observed a downregulation of Hsp70 compared to other Hsps [ 33 ].…”