Targeting heat shock protein 27 (HspB1) interferes with bone metastasis and tumour formation in vivo

Abstract

Background:The small stress heat shock protein 27 (Hsp27) has recently turned as a promising target for cancer treatment. Hsp27 upregulation is associated with tumour growth and resistance to chemo- and radio-therapeutic treatments, and several ongoing drugs inhibiting Hsp27 expression are under clinical trial. Hsp27 is now well described to counteract apoptosis and its elevated expression is associated with increased aggressiveness of several primary tumours. However, its role in the later stage of tumour progression and, more specifically, in the later and most deadly stage of tumour metastasis is still unclear.Methods/results:In the present study, we showed by qRT–PCR that Hsp27 gene is overexpressed in a large fraction of the metastatic breast cancer area in 53 patients. We further analysed the role of this protein in mice during bone metastasis invasion and establishment by using Hsp27 genetically depleted MDA-MB231/B02 human breast cancer cell line as a model. We demonstrate that Hsp27 silencing led to reduced cell migration and invasion in vitro and that in vivo it correlated with a decreased ability of breast cancer cells to metastasise and grow in the skeleton.Conclusion:Altogether, these data characterised Hsp27 as a potent therapeutic target in breast cancer bone metastasis and skeletal tumour growth.

Mitogen-Activated Protein Kinase–Activated Protein Kinase 2 in Neuroinflammation, Heat Shock Protein 27 Phosphorylation, and Cell Cycle: Role and Targeting

“…Furthermore, the Hsp27 gene was found to be overexpressed in a large fraction of the metastatic breast cancer patients. Depletion of Hsp27 in a human breast cancer cell line MDA-MB231/B02 reduced cell migration and invasion, and this attenuation of invasion correlated in vivo with a decreased ability of breast cancer cells to metastasize and grow in the skeleton (Gibert et al, 2012). In another comprehensive study, down-regulation of Hsp27 in MDA-MB-436-A breast cancer cells induced long-term dormancy in vivo (Straume et al, 2012).…”

Small heat shock proteins in ageing and age-related diseases

“…The importance of angiogenesis and lymphangiogenesis in cancer development is fundamental, since tumour growth and metastasis primarily depend on the formation of new vessels (Hanahan and Weinberg 2011). HSPB1 increases cancer cell motility, and its overexpression and phosphorylation are associated with increased metastatic and invasive potential of cells both in vivo and in vitro in various cancer types (Gibert et al 2012;Voll et al 2014;Yang et al 2010). Moreover, alpha-crystallins play an important role in cell motility and invasion.…”

Upregulation of heat shock protein 27 confers resistance to actinomycin D‐induced apoptosis in cancer cells

“…Conversely, suppression of HSP27 leads to long-term dormancy in human breast cancer, owing to inhibition of tumor angiogenesis [21]. Moreover, HSP27 silencing can inhibit breast cancer bone metastasis [22]. In addition, HSP27 expression can be induced by anticancer agents, such as 17-AAG and doxorubicin [6,23].…”

“…Mammalian HSPs have been classified into six families according to their molecular size: HSP100, HSP90, HSP70, HSP60, HSP40, and small HSPs (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). HSP90 regulates the stability of a diverse set of critical client proteins, including protein kinases (e.g.…”