Researchers at the University of Illinois say they have discovered a previously unknown mechanism by which estrogen prepares cells to divide, grow and, in the case of estrogen-positive breast cancers, resist cancer drugs. The scientists point out that the work reveals new targets for breast cancer therapy and will help doctors predict which patients need the most aggressive treatment.
The team reported its findings (“Anticipatory estrogen activation of the unfolded protein response is linked to cell proliferation and poor survival in estrogen receptor α-positive breast cancer”) in Oncogene.
Estrogen pre-activates the unfolded-protein response (UPR), a pathway that normally protects cells from stress. The UPR spurs the production of molecular chaperones that prepare cells to divide and grow. Without chaperone proteins to do the work of folding and packaging other proteins, cells (including cancer cells) cannot divide. For this reason, chaperones are a popular target for new cancer therapies.
Activation of the UPR is known as a normal response to stress, e.g., when a cell lacks adequate oxygen or nutrients, or is exposed to cancer-killing drugs. UPR activation prepares the cell for major changes associated with cell growth, division, and survival under stress.
It wasn't known before this study, however, that estrogen initiates this pathway before such stresses appear, said University of Illinois biochemistry professor David Shapiro, Ph.D.
“This is a new role for estrogen in the pathology of cancer,” said Dr. Shapiro. “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 its receptor it sparks a cascade of molecular events in the cell. A key event occurs when a channel opens in the membrane of a compartment that stockpiles calcium, and calcium floods into the cell.
“That’s a signal to activate the UPR pathway, the stress pathway,” noted Dr. Shapiro. “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 UPR also is a mediator of cell death. If a normal cell is exposed to too much stress, the stress response spurs apoptosis; in cancer, however, mild activation of the UPR by estrogen blunts this cell-death pathway, allowing cancer cells to survive and even resist drugs, the researchers found.
The team also looked at the expression of UPR-related genes in publicly available data from samples of breast tumors obtained from women who had been diagnosed up to 15 years prior. The analysis revealed that among women with estrogen-receptor-positive breast cancer who underwent tamoxifen therapy, breast cancer was 3.7 times more likely to recur in those overexpressing the UPR. Ten years after a breast cancer diagnosis, only 15% of those with the highest level of UPR-gene expression were disease-free, compared with 80% of women with minimal UPR expression.
“Analysis of data from ERα+ breast cancers demonstrates elevated expression of a UPR gene signature that is a powerful new prognostic marker tightly correlated with subsequent resistance to tamoxifen therapy, reduced time to recurrence, and poor survival,” wrote the investigators. “Thus, as an early component of the E2-ERα proliferation program, the mitogen estrogen drives rapid anticipatory activation of the UPR. Anticipatory activation of the UPR is a new role for estrogens in cancer cell proliferation and resistance to therapy.”
Dr. Shapiro adds that the new marker helps identify breast cancers that are likely to be highly aggressive and therefore require intensive therapy.