Scientists discover a new role for estrogen in the pathology of breast cancer

Scientists 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 researchers say the work reveals new targets for breast cancer therapy and will help doctors predict which patients need the most aggressive treatment.

The University of Illinois team reports its findings in the journal Oncogene.

Estrogen pre-activates the unfolded-protein response (UPR), a pathway that normally protects cells from stress, the researchers report. 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 - when a cell lacks adequate oxygen or nutrients, for example, 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, who led the new analysis with lead author, M.D.-Ph.D.-student Neal Andruska.

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

Breast cancer affects one in eight women during their lives. Breast cancer kills more women in the United States than any cancer except lung cancer. No one knows why some women get breast cancer, but there are a number of risk factors. Risks that you cannot change include

Age - the chance of getting breast cancer rises as a woman gets older
Genes - there are two genes, BRCA1 and BRCA2, that greatly increase the risk. Women who have family members with breast or ovarian cancer may wish to be tested.
Personal factors - beginning periods before age 12 or going through menopause after age 55

Other risks include being overweight, using hormone replacement therapy (also called menopausal hormone therapy), taking birth control pills, drinking alcohol, not having children or having your first child after age 35 or having dense breasts.

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," 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."