Stress response protects breast cancer cells from antiestrogenics

A natural stress response in cells appears to be the culprit that makes breast cancer cells become resistant to antiestrogenic agents. This finding opens up the possibility that the biochemical molecules involved in this response could serve as a new therapeutic target.

Many breast cancers that were once controlled by antiestrogenic drugs become resistant to these agents for reasons that are not understood. Now, however, researchers from Georgetown Lombardi Comprehensive Cancer Center—part of Georgetown University Medical Center in Washington, D.C.—have found that breast cancer cells protect themselves against the antiestrogenic agents tamoxifen and fulvestrant by switching on the unfolded protein response (UPR). This intracellular process is normally employed when proteins produced do not have the right shape—they are improperly folded. Once the UPR is initiated, the cell can activate either a prosurvival pathway or a process that ultimately destroys the cell.

The cells studied by Ayesha Shajahan, PhD, and colleagues all waited out the attack, allowing them to resist the anticancer treatment. “We found that antiestrogen-resistant cancer cells are much more likely to turn on the prosurvival pathway than are cells that are sensitive to estrogen,” explained Shajahan in a statement describing his team's research results, which were presented at the annual meeting of the American Association for Cancer Research, held April 2-6, 2011, in Orlando, Florida. 

The investigators also found that the antiestrogen-resistant breast cancer cells overexpress a protein (X-box binding protein 1, or XBP1), which turns on UPR signaling, and that specific resistance to fulvestrant occurs because of the overexpression of an XBP1 subtype, XBP1(s).

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