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.”
The stress-response pathway induces the production of chaperone proteins.
“I like to think of this pathway as an assembly line,” Shapiro said. “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.”
What is the difference between invasive and non-invasive breast cancer?
Invasive breast cancer - the cancer cells break out from inside the lobules or ducts and invade nearby tissue. With this type of cancer, the abnormal cells can reach the lymph nodes, and eventually make their way to other organs (metastasis), such as the bones, liver or lungs. The abnormal (cancer) cells can travel through the bloodstream or the lymphatic system to other parts of the body; either early on in the disease, or later.
Non-invasive breast cancer - this is when the cancer is still inside its place of origin and has not broken out. Lobular carcinoma in situ is when the cancer is still inside the lobules, while ductal carcinoma in situ is when they are still inside the milk ducts. “In situ” means “in its original place”. Sometimes, this type of breast cancer is called “pre-cancerous”; this means that although the abnormal cells have not spread outside their place of origin, they can eventually develop into invasive breast cancer.
What are the signs and symptoms of breast cancer?
A symptom is only felt by the patient, and is described to the doctor or nurse, such as a headache or pain. A sign is something the patient and others can detect, for example, a rash or swelling.
The first symptoms of breast cancer are usually an area of thickened tissue in the woman’s breast, or a lump. The majority of lumps are not cancerous; however, women should get them checked by a health care professional.
According to the National Health Service, UK, women who detect any of the following signs or symptoms should tell their doctor:
A lump in a breast
A pain in the armpits or breast that does not seem to be related to the woman’s menstrual period
Pitting or redness of the skin of the breast; like the skin of an orange
A rash around (or on) one of the nipples
A swelling (lump) in one of the armpits
An area of thickened tissue in a breast
One of the nipples has a discharge; sometimes it may contain blood
The nipple changes in appearance; it may become sunken or inverted
The size or the shape of the breast changes
The nipple-skin or breast-skin may have started to peel, scale or flake.
The UPR also is a mediator of cell death. If a normal cell is exposed to too much stress, the stress response spurs apoptosis, a kind of cellular suicide. 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.
“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,” Shapiro said.
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 percent of those with the highest level of UPR-gene expression were disease-free, compared with 80 percent of women with minimal UPR expression.
“Our marker helps identify breast cancers that are likely to be highly aggressive and therefore require intensive therapy,” Shapiro said.
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U. of I. graduate student Xiaobin Zheng, postdoctoral researcher Xujuan Yang and food science and human nutrition professor William Helferich contributed to the research.
The National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health funded the research.
Editor’s notes:
To reach David Shapiro, call 217-333-1788; email .(JavaScript must be enabled to view this email address).
The paper, “Anticipatory Estrogen Activation of the Unfolded Protein Response is Linked to Cell Proliferation and Poor Survival in Estrogen Receptor Alpha Positive Breast Cancer,” is available to members of the media from the U. of I. News Bureau.
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Diana Yates
.(JavaScript must be enabled to view this email address)
217-333-5802
University of Illinois at Urbana-Champaign