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Beating the odds. Breast cancer: your role in prevention

illustration: Rafael Lopez

“But I’ve been taking my vitamins and going to the gym … I’m a healthy person. Why do I have breast cancer? Why me? Did I get this from my mother? Will I pass this on to my daughter?”

The truth is that no one knows, at least most of the time. Researchers do know this: In cancer, the body’s regular process of renewal breaks down, and cells multiply out of control — then hidden genetic errors appear to kick off and encourage the process.

These genetic errors do not seem to act alone. Research shows that environmental factors, diet and lifestyle also seem to influence risk. What matters more: the inherited patterns that mark women’s genetic blueprint, or women’s lifestyles? 

As science debates the question, City of Hope researchers pursue answers. They analyze the genes that might drive tumors, screen high-risk women to determine their inherited genetic risk of breast cancer, and work on ways to prevent breast cancer’s onset and recurrence. By tackling risk both from the genes within the body as well as the lifestyle factors that influence it, they aim to help women to survive breast cancer and reduce the chance of developing cancer altogether.

How much is in the cards?

“When it comes to cancer, especially breast cancer,” said Thehang Luu, M.D., assistant professor in the Division of Medical Oncology & Therapeutics Research, “we always wonder, ‘are we born with it, is it in our genes, or is it something environmentally
induced?’ Certainly, some women face risk factors like heredity and ancestry.”

Inheritance of mutations in certain genes called tumor suppressor genes causes about 5 to 10 percent of breast cancer cases, according to researchers. These genes are supposed to keep breast cells growing normally and prevent cancer, but when they are abnormal, or mutated, they are linked to greater breast cancer risk. The most common genes associated with hereditary breast cancer are the BRCA genes. Women with BRCA1 or BRCA2 mutations may have a family history of early onset breast cancer, ovarian cancer or both. Men with these genetic mutations face risks, too: BRCA2 is associated with male breast and prostate cancers.

Researchers at City of Hope are studying various kinds of mutations in these genes and how much each variation raises the risk of breast cancer, as well as investigating the prevalence of risk-raising mutations in different ethnic groups.

“We don’t know in about 90 to 95 percent of the patients what caused their breast cancer, so you cannot pinpoint it down to one particular genetic mutation,” said Somlo. “So, the short answer to the ‘environment- versus-genetics’ question is ‘both.’”

He cites the example of second-generation Japanese-American women. Research shows that breast cancer risk rises significantly in these women, compared to women living in Japan, and some believe that dietary changes may be to blame. Environmental factors matter.

Genetic variables

Beginning in 1990, the Human Genome Project sought to determine the sequence of chemical base pairs that make up DNA and to identify the more than 35,000 genes of the human genome.  News stories about the studies may have led people to believe that genes determine health fate, said Jeffrey N. Weitzel, M.D., director of the Department of Clinical Cancer Genetics and the Cancer Screening & Prevention Program℠. This is partially true.

Some genes strongly influence breast cancer risk; others only moderately affect it, Weitzel said, and moderate-risk genes are more common.

“Unless they are in a specific sort of alignment, however, these moderate-risk genes don’t necessarily cause a problem for most people,” he said. “That’s where we’re facing the greatest challenges right now: differentiating those moderate-risk genes from the high-risk ones.” Researchers want to understand how moderate-risk genes affect the average woman’s breast cancer risk.

“Can you prevent a mutation? Of course not,” said Weitzel. “Can you lower the risk of cancer or enhance the chance of finding it at an earlier, more curable stage? Yes. Modifying environmental or behavioral influences such as weight, diet and exercise affects outcomes.”

illustration: Rafael Lopez

Researchers continue to learn about the genetic underpinnings of breast cancer, seeking to understand how genetic mutations that accumulate over time might drive cancer development. Breast cancer researcher Susan Kane, Ph.D., professor in the Department of Surgical Research, though, has noted a common frustration shared by breast cancer researchers and patients: Knowledge does not necessarily yield immediate answers.

“We can detect breast cancer much earlier, diagnose it much more accurately and subcategorize it into different types based on gene expression patterns,” she said. “But that doesn’t necessarily help us yet in making decisions about therapy and in having any more certainty in the likelihood of success or failure with particular types of therapy.

“So that’s really the Holy Grail to me: trying to match what we are learning about genetic changes, environmental influences and gene expression patterns with specific therapies that we think are going to be the most effective.”

For Kane, the most interesting work being done in this field is trying to understand the molecular activity surrounding different kinds of cancer. Identifying the specific genes that are turned on or off in breast cancer may yield valuable clues.

The role of estrogen

One of the factors that influences risk is a hormone essential to women: estrogen.

Reproductive factors linked to estrogen and other female hormones clearly influence disease risk. Starting menstruation later and entering menopause earlier, for example, reduce a woman’s lifetime exposure to large amounts of estrogen coursing through her body — and reduce the risk of developing breast cancer. Having children before age 30 and breastfeeding also reduces incidence. Yet, some of these factors are “more history than habits,” Weitzel said.

For years, postmenopausal women were routinely advised to use hormone replacement therapy (HRT) to prevent cardiovascular disease and osteoporosis and lessen symptoms such as hot flashes. In 2002, much-publicized results from the Women’s Health Initiative Trial for Hormone Replacement Therapy prompted many to stop HRT. The trial suggested that HRT — particularly estrogen combined with progesterone — increased breast cancer risk, so many women stopped taking the drugs. Afterward, breast cancer incidence began to decline.

“Clearly, hormones are a major part of the development of breast cancer,” said Joanne Mortimer, M.D., vice chair and professor in the Division of Medical Oncology & Therapeutics Research and associate director for affiliate programs. Research shows that about 70 percent of breast cancers depend on estrogen to grow.

Two clinical trials involving Shiuan Chen, Ph.D., director of the Department of Surgical Research and a co-director of the Breast Cancer Program, and Melanie Palomares, M.D., assistant professor in the divisions of Population Sciences and Medical Oncology & Therapeutics Research and a staff physician in the Department of Clinical Cancer Genetics, are investigating ways to lower hormone exposure in a unique way: by blocking a protein called aromatase. 

Aromatase is the enzyme that converts male hormones, androgens, into estrogens. After menopause, blocking aromatase can halt the most significant source of estrogen in the body, so new aromatase-inhibiting drugs have become a big part of physicians’ strategies in recent years to remove breast cancer’s “fuel” and keep the disease from recurring after treatment.

Since aromatase comes from peripheral tissues such as fat cells, its presence is “probably the mechanism linking the risk factor obesity to breast cancer,” explained Palomares.

Chen and Palomares are examining whether substances from natural sources — grape seed extract and mushrooms — can block aromatase and lower breast cancer risk. 

Chen’s laboratory was one of three labs that originally characterized the human aromatase gene. Chen is widely known for his work in understanding drugs that inhibit aromatase. His lab is conducting extensive studies to evaluate why people become resistant to these drugs, and is developing strategies to reduce the drugs’ side effects.

A personal prevention menu

“There is a lot women can do to affect their risk of developing breast cancer,” Luu said.

Diet plays an important role. “We have more food choices available to us than previous generations, but not necessarily healthier,” she said.

She advocates a diet rich in fruits and vegetables. Luu also believes such foods that are purchased within 20 miles of where they are grown provide the most benefit, since they are more likely to be picked at the peak of freshness and retain 80 to 90 percent of their nutrients.  Limiting alcohol consumption and avoiding smoking also lowers risk.

Exercise also has been shown to reduce the risk of developing breast cancer (not to mention warding off diabetes, osteoporosis and cardiovascular disease). Studies show women with breast cancer who exercise have more stamina during their treatments, and that such activity may help prevent recurrence, as well.

In addition to lifestyle choices, measures such as breast self-exams and regular mammograms can detect the disease early, greatly improving the odds for successful treatment.

And genetic testing is beneficial — for some individuals. Anyone with a personal or family history of breast or colon cancer before age 50, a woman who has had ovarian cancer at any age or those with a personal or family history of cancer in several close relatives on the same side of the family is a prime candidate for this testing, which scans DNA for inherited genetic mutations linked to cancer.

illustration: Rafael Lopez

Workouts work

There is perhaps no more renowned expert in the link between regular exercise and breast cancer risk reduction than Leslie Bernstein, Ph.D., director of the Department of Cancer Etiology in the Division of Population Sciences and professor and dean for faculty development.

Her first study demonstrating that link was published in the Journal of the National Cancer Institute in 1994. Just weeks before, scientists had identified BRCA1 and BRCA2 genes. “The news at that time was somewhat frightening and also good,” Bernstein said. “Women could be tested and they’d know if their chances were higher for getting breast cancer. And my study provided some hope, because it showed that physically active women experienced lower breast cancer risk.

“Physical activity was the good news story. It hit everywhere, and it hasn’t stopped,” she added.

Bernstein began her research by searching for something that could modulate women’s hormones, which were already known to influence breast cancer risk. Recalling her own teenage years as an athlete with altered menstrual cycle patterns, she turned to exercise as a target.

Her first study focused on moderately active teenage girls. “We measured hormone levels during their menstrual cycles, and saw that they didn’t have the usual periodic increases of estrogen and spikes of progesterone,” she said. “From those data, we predicted that physical activity would reduce breast cancer risk.”

In 1995, Bernstein and her colleagues started the California Teachers Study. Funded by the National Cancer Institute until 2009, the study follows 133,500 current and former educators, comparing those who developed cancer to those who did not. The study has confirmed activity’s link to reduced risk.“Women who were the most active when they were younger are less likely to die of breast cancer,” she said. Bernstein, who is the principal investigator for the study, and her colleagues continue to follow the women.

She has conducted six other studies confirming that exercise helps prevent breast cancer, mitigate its effects and decrease the chance of recurrence. More than 30 other studies have validated her findings. 

In recognition of her work, Bernstein received the 2007 Komen Brinker Award for Scientific Distinction in breast cancer clinical research from Susan G. Komen for the Cure and the Cancer Prevention Award for Excellence in Cancer Prevention Research from the American Association for Cancer Research.

Bernstein practices what she preaches, too. She has maintained her weight by eating a balanced diet and exercising regularly.  She suggests that all women exercise at least three to four hours per week.

When Bernstein published the results from the first study, she encountered skeptical media who asked, “So what if you’re wrong?”

“And I said, ‘So what?’ Even if it doesn’t prevent breast cancer, it might prevent you from dying from it if you do happen to get it,” she said. “Your overall health will improve, as well.

“This potential impact on prognosis following breast cancer is now an area of great interest in the field. Preliminary studies, including the California Teachers Study, indicate that women who exercise after diagnosis benefit in terms of lower chances of recurrence and better survival,” she added.

While researchers strive to define the role of genetics and environment in breast cancer risk, women can help themselves by fully exploring their family medical history, sharing it with their physicians and making smart lifestyle choices.

“Controlling what you can control — your lifestyle — really may have a meaningful impact,” said Bernstein.

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