New estrogen-related breast cancer pathway detected

The unfolded-protein response pathway - activated by estrogen - allows cancer cells to survive and even resist cancer drugs.

The unfolded-protein response (UPR) pathway protects cells from stress
and initiates the production of "chaperone proteins." These proteins
fold and package other proteins, preparing cells to divide and grow.
Because these chaperones are essential to the division of cells, they
are now a popular target for cancer treatments.

"I like to think of this pathway as an assembly line," University of
Illinois biochemistry professor David Shapiro explains. "In order for
cells to divide, you're going to have to produce a lot more proteins.
The chaperones help you to package, fold up and ship all these
proteins."

Scientists know that the UPR is activated as part of a stress
response in scenarios when a cell is lacking oxygen or nutrients or is
attacked by drugs. The activation of the UPR prepares the cell for
growth, division and survival under stress.

The major new finding reported by the University of Illinois team is
that the UPR is initiated by estrogen even before the emergence of any
stresses associated with UPR activation.

Prof. Shapiro explains:

"This is a new role for estrogen in the pathology of cancer. 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."

Prof. Shapiro and colleagues found the signal that activates the UPR
pathway occurs when estrogen binds to its receptor, which causes a
stockpile of calcium
to flood into the cell. "It's also a signal that many researchers think
has something to do with cell proliferation," says Prof. Shapiro. "The
calcium itself may be a proliferation signal."

As well as protecting cells, though, the UPR can also trigger apoptosis -
a kind of "cellular suicide" - in cases where a normal cell is exposed
to too much stress. However, when the UPR is activated by
estrogen, this cell-suicide response is "blunted," allowing cancer cells
to survive and resist drugs.

UPR-related gene expression as prognostic marker

In another arm of the study, the researchers carried out a computer analysis of breast cancer data - investigating UPR-related gene expression - from women who had been diagnosed up to 15 years prior.

The results demonstrate that among women with estrogen-receptor-positive breast cancer who received tamoxifen as a treatment,
those with "overexpressed" UPR were 3.7 times more likely to have breast cancer recurrence.

Looking at outcomes 10 years after diagnosis, 15% of women with the
highest level of UPR-gene expression were cancer-free, compared with 80%
of women with the lowest level of UPR expression.

Prof. Shapiro says the computer analysis shows that "UPR activation is a
very powerful prognostic marker of the course of a woman's disease."

"Our marker helps identify breast cancers that are likely to be highly
aggressive and therefore require intensive therapy," he adds.

Previous research has also found that UPR may contribute to sudden death in heart failure. In 2013, a study published in Circulation: Arrhythmia and Electrophysiology suggested that the UPR may explain the loss of many useful proteins that protect against heart failure.

Written by David McNamee