HSP70s in Breast Cancer: Promoters of Tumorigenesis and Potential Targets/Tools for Therapy

Abstract

The high frequency of breast cancer worldwide and the high mortality among women with this malignancy are a serious challenge for modern medicine. A deeper understanding of the mechanisms of carcinogenesis and emergence of metastatic, therapy-resistant breast cancers would help development of novel approaches to better treatment of this disease. The review is dedicated to the role of members of the heat shock protein 70 subfamily (HSP70s or HSPA), mainly inducible HSP70, glucose-regulated protein 78 (GRP78 or HSPA5) and GRP75 (HSPA9 or mortalin), in the development and pathogenesis of breast cancer. Various HSP70-mediated cellular mechanisms and pathways which contribute to the oncogenic transformation of mammary gland epithelium are reviewed, as well as their role in the development of human breast carcinomas with invasive, metastatic traits along with the resistance to host immunity and conventional therapeutics. Additionally, intracellular and cell surface HSP70s are considered as potential targets for therapy or sensitization of breast cancer. We also discuss a clinical implication of Hsp70s and approaches to targeting breast cancer with gene vectors or nanoparticles downregulating HSP70s, natural or synthetic (small molecule) inhibitors of HSP70s, HSP70-binding antibodies, HSP70-derived peptides, and HSP70-based vaccines.

The Role of Heat Shock Protein 70 Subfamily in the Hyperplastic Prostate: From Molecular Mechanisms to Therapeutic Opportunities

“…Once unfolded proteins accumulate within the ER, three SSTs dissociate from GRP78, and these liberated SSTs are able to regulate certain signal pathways and activate downstream effectors [63]. The products of ER stress-responsive genes include calreticulin, the component of ER-associated protein degradation (ERAD) serving for the proteolysis, and inducible GRPs (GRP170, GRP94, GRP78, GRP75) that catalyze either disaggregation or refolding of stress-damaged proteins within the ER and mitochondria in an ATP-dependent manner [17]. When accumulation of unfolded and misfolded proteins is reduced, GRP78 expression and its binding to three SSTs return to normal; however, once UPR fails to restore homeostasis, uncontrolled UPR leads to macroautophagy or cellular apoptosis [64,65].…”

“…Based on molecular weight, HSPs are commonly classified into six subfamilies: HSPH (HSP110), HSPC (HSP90), HSPA (HSP70), DNAJ (HSP40), HSPB (small HSPs (sHSPs)), as well as chaperonin families: HSPD/E (HSP60/HSP10) and CCT (cytosolic chaperonin TCP1 ring complex (TRIC)) [16]. The members of the HSP70 subfamily weigh 68-78 kDa and primarily include HSP70, glucose-regulated protein 78 (GRP78) and mortalin [17]. It has been noted that HSP70s modulate multiple biological processes associated with the development of BPH, such as cell survival and proliferation, cell apoptosis and the androgen receptor (AR) pathway [16,18,19].…”

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

“…Mortalin (Grp75) is known to contribute to the development and pathogenesis of BC. It can promote metastasization and angiogenesis in DC cell lines, e.g., MCF-7, and SK-BR-3 lines [ 79 , 80 ]. The knockdown of Mortalin in MCF-7 and SK-BR-3 cells leads to overexpression of epithelial markers, such as ZO-1 and E-cadherin; however, mesenchymal markers showed low expression [ 79 , 80 ].…”

“…It can promote metastasization and angiogenesis in DC cell lines, e.g., MCF-7, and SK-BR-3 lines [ 79 , 80 ]. The knockdown of Mortalin in MCF-7 and SK-BR-3 cells leads to overexpression of epithelial markers, such as ZO-1 and E-cadherin; however, mesenchymal markers showed low expression [ 79 , 80 ]. Mortalin promoted the endothelial-to-mesenchymal transition (EMT) in BC via the Wnt/β-catenin signaling pathway [ 79 ].…”

“…Elevated extracellular Hsp70 levels could propagate chronic inflammation, which could in turn suppress the antitumor immune responses [ 72 ]. Hsps have been reported to elicit specific humoral immunity in BC patients when released into the extracellular environment [ 80 , 153 ]. Antibodies specific for Hsps have been found in the blood of women with BC with improved survival [ 154 ].…”