Abstract
Breast cancer (BC) is one of the major causes of cancer death in women and is closely related to hormonal dysregulation. Estrogen receptor (ER)-positive BCs are generally treated with anti hormone therapy using antiestrogens or aromatase inhibitors. However, BC cells may become resistant to endocrine therapy, a process facilitated by autophagy, which may either promote or suppress tumor expansion. The autophagy facilitator HSPB8 has been found overexpressed in some BC. Here we found that HSPB8 is highly expressed and differentially modulated by natural or synthetic selective ER modulators (SERMs), in the triple-positive hormone-sensitive BC (MCF-7) cells, but not in triple-negative MDA-MB-231 BC cells. Specific SERMs induced MCF-7 cells proliferation in a HSPB8 dependent manner whereas, did not modify MDA-MB-231 cell growth. ER expression was unaffected in HSPB8-depleted MCF-7 cells. HSPB8 over-expression did not alter the distribution of MCF-7 cells in the various phases of the cell cycle. Conversely and intriguingly, HSPB8 downregulation resulted in an increased number of cells resting in the G0/G1 phase, thus possibly reducing the ability of the cells to pass through the restriction point. In addition, HSPB8 downregulation reduced the migratory ability of MCF-7 cells. None of these modifications were observed, when another small HSP (HSPB1), also expressed in MCF-7 cells, was downregulated. In conclusion, our data suggest that HSPB8 is involved in the mechanisms that regulate cell cycle and cell migration in MCF-7 cells.
Highlights
Breast cancer (BC) is the most frequent cause of cancer death in women in underdeveloped countries, while in western countries is the second cause of death, after lung cancer [1]
Expression analysis performed using real-time RT-PCR showed that HSPB8 mRNA is highly expressed in iPSCs, in BC cells (MCF7) and in hepatocellular carcinoma (HepG2), while its expression is much lower in prostate cancer (PC) cells (PC3 and DU145 cells) and in melanoma cells (BML) (Figure 1, panel A)
When HSPB8 protein levels were quantified in Western blot analysis (Figure 1, panel B), we found that MCF-7 cells were characterized by very high content of HSPB8 as compared to the other cell clones selected
Summary
Breast cancer (BC) is the most frequent cause of cancer death in women in underdeveloped countries, while in western countries is the second cause of death, after lung cancer [1]. The SERMs mechanism of action depends on three interdependent factors: the level of ER isoform (ERα or ERβ) expression in a given target tissue, the different conformational changes of ERs induced by a given SERM and the binding of transcriptional www.impactjournals.com/oncotarget regulatory proteins to ERs. In several cases, BC cells become resistant to these anti-hormonal therapies [7], giving rise to more aggressive tumors (e.g. tamoxifenresistant BC). It has been recently proposed that the mechanism responsible for anti-hormonal resistance in BC is facilitated by autophagy [8], a process responsible for the degradation of damaged proteins or organelles [9]. HSPB8 or BAG3 silencing results in disorganization of actin-rich retraction fibers and alters spindle orientation: HSPB8-BAG3 complex may mediated quality control mechanism during mitotic processes activated in proliferating cells [18]
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