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The unfolded protein response (UPR) in antiestrogen resistance in breast cancer
Author(s) -
Shajahan Ayesha N.,
Hickman F. Edward,
Facey Caroline,
Cook Katherine,
Clarke Robert
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.806.2
In 2011, there will be almost 192,000 newly diagnosed cases of invasive breast cancer in the U.S. with estrogen receptor alpha positive tumors. For these patients, endocrine therapy, administered as an antiestrogen, e.g., Tamoxifen, is the least toxic and most effective means to manage their cancer but antiestrogen resistance remains a significant clinical problem. We have shown that antiestrogen resistant breast cancer cells over‐express X‐Box Binding Protein 1 (XBP1). IRE1alpha, ATF6 and PERK are endoplasmic reticulum proteins that sense cellular stress in the unfolded protein response (UPR) ‐ an adaptive signaling pathway that allows cells to survive the accumulation of unfolded proteins. XBP1 is an obligate component in both the IRE1alpha and ATF6 arms of the UPR. Here we show that antiestrogen resistant breast cancer cells survive by activating prosurvival autophagy through XBP1‐mediated UPR. These cells showed an increase in UPR signaling as detected by increased expression of BiP/GRP78. Antiestrogen sensitive cells over‐expressing XBP1(S) showed increased level of basal and drug‐induced autophagy as measured by cleaved LC3BII protein fragment, GFP‐LC3 activity, and reduced expression of p62/SQSTM1. Thus, our results highlight a novel mechanism in breast cancer cells that leads to antiestrogen resistance.

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