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Review
. 2017 Nov 16;15(1):109.
doi: 10.1186/s12915-017-0449-4.

Targeting protein quality control pathways in breast cancer

Sara Sannino, Jeffrey L Brodsky  1
Affiliations
Review

Targeting protein quality control pathways in breast cancer

Sara Sannino et al. BMC Biol. .

Abstract

The efficient production, folding, and secretion of proteins is critical for cancer cell survival. However, cancer cells thrive under stress conditions that damage proteins, so many cancer cells overexpress molecular chaperones that facilitate protein folding and target misfolded proteins for degradation via the ubiquitin-proteasome or autophagy pathway. Stress response pathway induction is also important for cancer cell survival. Indeed, validated targets for anti-cancer treatments include molecular chaperones, components of the unfolded protein response, the ubiquitin-proteasome system, and autophagy. We will focus on links between breast cancer and these processes, as well as the development of drug resistance, relapse, and treatment.

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Figures

Fig. 1.
Fig. 1.
Schematic representation of secretory protein folding and quality control, the unfolded protein response pathway, and the heat shock response. In the endoplasmic reticulum, unfolded proteins (black lines) can be recognized and bound by chaperones, such as BiP (yellow circles). The increase in the concentration of BiP-unfolded protein complexes in the endoplasmic reticulum favors induction of the unfolded protein response (UPR). The UPR is regulated by ATF6 (light blue rectangle), PERK (green dimers), and IRE1 (orange dimers), which reside in the endoplasmic reticulum membrane. Upon activation, the UPR can increase cellular folding capacity by increasing chaperone synthesis, inducing endoplasmic reticulum expansion, and increasing the concentration of components of the endoplasmic reticulum associated degradation (ERAD) machinery. During ERAD, unfolded proteins in the endoplasmic reticulum are recognized, ubiquitylated by E3 ubiquitin ligases, and retrotranslocated via the action of p97 (blue circle), an AAA-ATPase, to the cytosol where they are degraded by the proteasome. Misfolded, aggregation-prone proteins, protein aggresomes, and damaged organelles can alternatively be targeted for autophagy via encapsulation in double membrane vesicles known as autophagosomes (light brown vesicles). LC3BII is an established marker of cellular autophagy and is associated with autophagosome membranes (light green circles), and proteins can be directed to autophagy degradation via HDAC6 (purple hexagon). Upon fusion with lysosomes (red vesicles), the material incorporated in the autophagolysosome is degraded (orange vesicles). In the absence of stress, HSF1, HSP90, HSP70, and HDAC6 can form a complex in the cytoplasm. During stress (for example, an increase in the concentration of unfolded protein or heat), HSF1 (orange rectangle) can translocate to the nucleus and induce the transcription of other proteins, like chaperones, to increase the cellular folding capacity. This is known as the heat shock response. At the same time, Hsp90 and Hsp70 (green and white rounded rectangles, respectively) are involved in cytoplasmic protein folding, dictating the fate of their clients. If the client fails to attain its final conformation, it will be ubiquitylated and degraded by the proteasome
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