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Life's work

Dr. Leigh Murphy has spent 30 years studying the effects of estrogen on the development of breast cancer. Now, she is poised to publish research that will help open the door to better treatment options for women fighting this disease.

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It really doesn't look like much - just a small, rectangular block of opaque paraffin, about two inches long, speckled with dark, pin-sized dots.

Indeed, it's the kind of thing that can easily get overlooked in a lab loaded with everything from beakers and hazardous chemicals and liquids to computers and other specialized equipment.

But there is more here than meets the eye. Just ask Dr. Leigh Murphy, Director of the Manitoba Breast Cancer Research Group, located within the Manitoba Institute of Cell Biology, a joint institute of the University of Manitoba and CancerCare Manitoba.

As Murphy explains, each pair of dots on the paraffin block is made up of miniscule core samples of tissue from a cancerous breast tumour. Place them under a microscope, and one is able to glimpse the biological data that explains how breast cancer develops - and, perhaps, how it can be stopped.

"It's amazing how much information is in these little black dots," she says as she cups one of the wax blocks in the palm of her hand.

Murphy should know. After all, she has spent more than 30 years examining tissue samples similar to the ones in her hand. In doing so, she has gained new insights into breast cancer, or more precisely, the role played by the hormone estrogen in the development of the disease, enough to write more than 140 research papers.

Now, after mining more of the data contained in those little black dots, Murphy is poised to publish the results of a new study, one that promises to change the way thousands of women are diagnosed and treated for breast cancer. The paper, when published, will be another highlight in Murphy's career, one that started on the other side of the world.

A native of Australia, Murphy was naturally drawn to science early in life. By the time she hit high school - where she excelled in math and science - she set her sights on becoming a teacher. But as she worked her way through a bachelor's of science degree and then an honour's degree in biochemistry at Sydney University, Murphy began to expand her scientific ambitions. By the time she was working on her PhD in reproductive endocrinology, Murphy began to examine the role estrogen played in the reproductive cycle of animals - especially sheep. She's been focused on the role of estrogen ever since.

Thirty years is a long time to spend in a lab pursuing one basic line of inquiry, but that is the nature of research. The life of a "basic scientist," as Murphy calls herself, is certainly not for the easily frustrated. Important breakthroughs do not happen overnight, nor are they generally the work of a single person. Murphy has dedicated her life to understanding the intricacies of the relationship between estrogen and breast cancer, as have others around the world. Together, in formal and informal networks, they share their knowledge and insights, building on each other's work, all with the same goal: to help conquer the disease. It's like fitting together the pieces of a jigsaw puzzle. Each piece is important, but only as it relates to the entire picture.

Murphy never tires of trying to solve the puzzle. When asked why, she immediately starts talking about the challenging and rewarding nature of the work. "It's an exciting field," she says. "The curiosity has always been there and it has always been fed."

But there are other motivations, as well. Friends of hers are living with or have died from breast cancer, she explains, and her husband, Liam Murphy, also died of cancer five years ago. "It does get personal," she adds quietly.

To understand the implications of Murphy's latest research project and how it may affect the diagnosis and treatment of women with breast cancer, it helps to have a basic understanding of how the disease works.

Simply put, cancer occurs when a group of abnormal cells develop and multiply out of control. These abnormal cells can circulate in the blood and the lymphatic system, or form lumps and tumours. Cells that divide are at a higher risk of developing cancer than cells that don't divide. That's why cancer is generally rare in tissues that don't divide, like nerve tissue, and is more common in tissues where cells divide frequently, such as skin, colon, uterine and breast tissues, according to The Biology of Breast Cancer, a posting on the Cornell University website.

Breast tissues are especially sensitive during puberty. The cells in the immature breast are not very efficient at repairing mutations and are more likely to attract cancer-causing agents, according to the Cornell posting. (After a woman's first fullterm pregnancy, breast cells develop into mature cells, which make milk and are less sensitive to DNA damage.) Interestingly, it may take years for cancerous breast tumours to develop, which is why breast cancer numbers rise as women get older, according to the website.

So what role does estrogen play in all this?

Essentially, estrogen is present in all vertebrates, both male and female. Females in particular know about the ups and downs of the estrogen supply. Estrogen kicks in for the natural development of reproductive organs like the uterus and breasts, but it is also necessary for the healthy development of the heart, bones, muscle, blood vessels and the brain.

For pre-menopausal women, too much estrogen causes breast swelling, heavy painful periods and premenstrual syndrome. For women in menopause, too little estrogen accounts for hot flashes, urinary tract infections and joint pain. It can also affect the health of your skin, hair and digestive tract.

But estrogen doesn't work alone. All the actions of estrogen in cells are controlled by estrogen receptors. (An estrogen receptor has been described by one writer for the New York Times as "a molecular docking site with which estrogen must unite if tissues of the uterus, breast or elsewhere are to respond to hormonal stimulation.")

In a normal situation, these receptors control the amount of estrogen received by the cell, essentially turning the hormone on and off, depending on the circumstances. But once in a while, the ability to control the level of activity of estrogen and its receptor is lost. Unchecked, the hormone and its receptor wreak havoc within the structure of breast tissue in the form of cancerous cells.

"We don't think estrogen actually causes breast cancer," says Murphy. "We think there is something else that causes a change in the cell, and estrogen fuels that. In other words, in breast cancer, there is a deregulation of estrogen (caused when estrogen receptors don't function properly or when there is too much estrogen and other associated hormones), and that fuels the growth of existing abnormal breast cells, which increases the risk of breast cancers dependent on estrogen (for growth)."

Not all breast tumours are estrogen-driven, but most are. In post-menopausal women, 70 per cent of breast cancers are fueled by estrogen. (The estrogen overload can be from either too much natural estrogen or the result of exposure to what are called environmental estrogens, usually from hormone replacement therapies, or possibly synthetic chemicals that can act like human estrogen in a woman's body. These so-called "mimic" estrogens are found in some pesticides, products associated with plastics, industrial chemicals, or in heavy metals like lead, mercury and cadmium).

The fact that estrogen drives breast tumours isn't a recent discovery. In 1896, Scottish surgeon Dr. George Beatson published a landmark paper on how he successfully treated three patients with breast cancer by the removing their ovaries. (In premenopausal women, ovaries secrete the most estrogen.) This work forms the basis of the current anti-hormonal treatment of breast cancer today.

But it wasn't until the discovery of estrogen receptors in the 1960s that scientists understood how the hormone worked in the delicate tissue structure.

Until the mid-1970s, most women with breast cancer were treated with chemotherapy and/or a radical mastectomy, which included the removal of breast, chest muscles and underarm lymph nodes. This would then be followed by radiation. Later, clinicians began to see positive results with a lumpectomy, which involved removal of the tumour and some of the surrounding tissue. By 1985, the lumpectomy, combined with radiation therapy, was found to be as effective as the mastectomy in terms of survival rates.

But the discovery that some breast cancer cells had an estrogen receptor (now known as estrogen receptor alpha, or ERa), opened the door for new targeted drug treatments that were less toxic than chemotherapy. The first of these estrogen-blocking drug treatments, also known as hormone treatment therapies, was tamoxifen. Tamoxifen has been routinely used to treat some breast cancers for over 25 years and has saved the lives of tens of thousands of women with breast cancer.

In theory, tamoxifen should have been able to inhibit the growth of all estrogen-driven tumours. But it didn't.

"One thing we knew," says Murphy, "is that for tamoxifen to work, we had to pick women whose breast tumours had estrogen receptors. But not all women whose breast tumours had estrogen receptors responded. So, for whatever reason, some of these estrogen receptor-positive tumours were resistant. And we didn't know why."

And the mystery deepened.

"The disease recurred in some patients who had initially responded to the anti-estrogen. So there were now two questions: First, why were some estrogen receptor-positive tumours resistant, and, second, after the initial response to the drug, why, in some women, did the disease come back?"

Murphy worked on these questions for years. One promising line of inquiry centred on whether a certain kind of protein in the cell was soaking up tamoxifen so that it couldn't effectively inhibit the cancerous growth. But none of her theories led to any breakthroughs.

Then, about 15 years ago, everything changed.

Until that time, Murphy, and everyone else working in the field of breast cancer, believed that there was only one estrogen receptor at play in estrogen-responsive cells, either normal or pathological. That changed in 1996 when a Swedish researcher discovered the presence of a second estrogen receptor (now known as estrogen receptor beta, or ERb).

The finding took Murphy's work in a new direction.

"Of course, when that was discovered, then everyone had to alter their understanding of estrogen action in any target tissue. No matter if it was breast, uterus, prostate, testes, cardiovascular or brain - we all had to stand back and say, ‘Whoa! There is another receptor that may work differently. How does that affect our understanding of how estrogen works?"

At first, Murphy waited to see if new research would establish whether ERb was present in breast tumours. When none was forthcoming, she and her team at the Manitoba Breast Cancer Group started their own research into the question. "I was waiting for someone to tell me whether it was in breast cancers. When nothing came out, I thought, ‘Oh well, we have to do this ourselves.'"

Just as well, as it turns out. "We were pretty good at doing that. I had a very skillful technician (Helmut Dotzlaw) and a very gifted post doc (Dr. Etienne Leygue) - who together developed a test to see if this second receptor is (present) in breast tumours, because we had to know if it is there. We had to know if it could be part of how estrogens - as well as the anti-estrogen drugs - work in breast cancer."

The team went to work. First, they retrieved samples of cancerous and normal breast tissue from the Manitoba Breast Tumour Bank. Located on the same floor as the Manitoba Breast Cancer Research Group and managed by the Manitoba Institute of Cell Biology, the bank was established in 1993 by pathologist Dr. Peter Watson, and contains 5,000 breast tumours going back to 1988. In other words, it is indispensible to the research work that goes on at the institute, and also supports local, national and international research outside of the institute.

The process of analyzing tissue samples is relatively straightforward - if you are a scientist. First, the ribonucleic acid (RNA is one of three macromolecules essential for life) from the tumour is extracted and then converted to deoxyribonucleic acid (DNA). Then the DNA ( which contains the genetic code for all living things) is amplified and stained with ethidium bromide, which binds to the DNA and makes it easier to see. A special camera, which employs UV light, is then used to view the size of the DNA piece. Then the exact nucleotide sequence of that piece of DNA can be determined. This is the unique fingerprint identifying the expression of ERb.

In 1997, one year after the discovery of a second receptor, Murphy and her team became the first to publish research confirming that ERb RNA was indeed present in some cancerous breast tissue as well as normal breast tissue. The research also showed that the second estrogen receptor operated differently than the first one, and was the only one present in a certain number of cancers.

To put these findings in context, it is important to remember that, at the time, a woman with breast cancer who was ERanegative (meaning she did not have high levels of estrogen receptor alpha) would generally not be eligible for treatment with tamoxifen. But Murphy's research raised another question: What about women with ERb? Could they benefit from treatment with tamoxifen?

Murphy was determined to find out.

First, she acquired an antibody for ERb (the antibody is used to make it easier to evaluate the status of the estrogen receptor protein). Then she went back to the tumour bank to retrieve samples of breast cancer tissue - remember the wax block with the black dots.

Through the review of hundreds of samples and a subsequent statistical analysis, Murphy was able to determine the following:

  • Women who were ERa-positive responded well to treatment with tamoxifen, as was to be expected. But those who expressed both ERa and ERb generally did better.
  • The two receptors - ERa and ERb - behave differently. A high expression, or level, of ERa was associated with cancer. Conversely, a low expression, or level, of ERb was also associated with cancer. In other words, it appeared that the two receptors worked in tandem (almost like a brake and an accelerator in a car) to regulate estrogen action. If one malfunctioned, then neither would work properly, and the estrogen activity in the cell would not be properly regulated.
  • Some women who were ERa-negative, but who had been treated with tamoxifen anyway (generally because they were not well enough to undergo chemotherapy) also sometimes responded positively to the drug. This was not expected.
  • The women who were ERa-negative but did respond positively to tamoxifen often had tumours that happened to be ERb-positive.

The findings were intriguing.

"The fact that some women who had ERb - but not ERa - responded to tamoxifen was very exciting," says Murphy. "Our data suggest that blocking the activity of this second receptor (ERb) in these breast cancers (with tamoxifen) could be a less toxic treatment option for this group of patients, who usually only have more toxic chemotherapy options."

While Murphy's data are being prepared for publication, it's not clear how long it will take for her research to be translated into actual treatment options for women. Her findings will have to be tested in a series of clinical trials, and it may be several years before they are completed. If the clinical trials support the research, thousands of women could benefit from an existing treatment, and, possibly, new emerging ERb-selective treatments.

Should all that come to pass, Murphy points out, it will be because of the thousands of women who have donated breast tissue to the tumour bank over the years. It is, after all, their contributions that have made it possible to create all those opaque paraffin blocks, speckled with dark, pin-sized dots. And gave Murphy a chance to discover what secrets they might contain.

Dolores Haggarty is a Winnipeg writer.

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