Signaling Cellular Stress

Researchers from the University of Illinois at Urbana-Champaign, USA, have discovered a new function for estrogen in the pathology of breast cancer (1). The hormone atypically activates a pathway called the unfolded protein response (UPR). UPR normally protects cells against stress by activating downstream pathways to reduce protein production and by increasing the protein folding capacity of the endoplasmic reticulum. UPR is inactive in healthy and unstressed cells, but overactive in numerous types of cancer, including breast tumors. Chronic activation of the pathway appears to facilitate the survival, proliferation, angiogenesis and treatment resistance of tumors.

In normal cells, the UPR is activated by the endoplasmic reticulum stress sensor, which responds to cell stresses such as hypoxia or an accumulation of unfolded protein (2). Acting via estrogen receptor α (ERα), estrogen induces rapid pre-activation of the UPR before normal stress signals are present. “This is a new role for estrogen in the pathology of cancer,” said David Shapiro, the biochemistry professor who led the study. “Others have shown that stress activates this pathway, helping to protect some tumors. What is new is our finding that estrogen can pre-activate this pathway to protect tumors.”

When estrogen binds to ERα, it initiates a series of molecular changes in the cell. One of these involves opening calcium channels in the endoplasmic reticulum, allowing calcium ions to flood the cell. “That’s a signal to activate the UPR pathway – the stress pathway,” Shapiro said. “It’s also a signal that many researchers think has something to do with cell proliferation. The calcium itself may be a proliferation signal.” The pathway induces additional chaperone production, which Shapiro refers to as an “assembly line” for protein packaging, and also mediates cell death. In a normal cell, excessive stress will induce apoptosis, but in a cancer cell with mild, ongoing UPR activation, the opposite occurs – the apoptosis pathway becomes more difficult to induce, allowing malignant cells to survive under conditions that would otherwise have caused their death.

By looking back at genetic data from breast tumor samples, the researchers were able to correlate UPR activation with disease outcome. They found that patients expressing the UPR signature had a higher rate of recurrence, reduced time to relapse and reduced overall survival. Ten years after diagnosis, only 15 percent of women with high UPR expression were disease-free, compared with 80 percent of women with minimal expression. “[Neal] Andruska, who spearheaded the research and carried out the computer analysis of the breast cancer data, found that UPR activation is a very powerful prognostic marker of the course of a woman’s disease,” said Shapiro. “Our marker helps identify breast cancers that are likely to be highly aggressive and therefore require intensive therapy.”

The function of estrogen in anticipatory activation of the UPR pathway was hitherto unknown, but suggests a new therapeutic target worthy of further investigation. For cancers that are resistant to current therapies, such knowledge can be useful in the development of new and effective treatments.