Finding the Breast Cancer Genes

Breast cancer is the most frequently diagnosed cancer worldwide, and is heavily publicized as the leading cause of cancer death for women in Britain and the second leading cause of cancer death for women in the United States.7 The news media, medical charities, and public health organizations in each country quote that a British woman has a 1-in-12 chance of developing invasive breast cancer during her lifetime, and that an American woman has a 1-in-8 chance. Although governments and medical charities (including the Imperial Cancer Research Fund and Cancer Research Campaign in Britain and the National Cancer Institute and American Cancer Society) have spent a considerable amount of money to look for a cause and to develop prevention and treatment strategies for the disease, neither an unequivocal cause nor a completely effective prevention, detection, or treatment strategy has yet been found. Mastectomy, which involves breast removal, not only has severe physiological and psychological effects but also doesn't completely eliminate the incidence of a first breast cancer or even the risk of recurrence.8 And radiation therapy and chemotherapy (a chemical treatment to kill tumor cells)—uncomfort-able procedures that induce considerable sickness and hair loss among patients—are still not completely reliable.9 Even technologies to detect cancer early are not entirely reliable. Mammographic screening, which involves breast imaging using low levels of radiation to detect tumors, is controversial; some argue that it is not useful to identify tumors in the denser breasts of young women, while others suggest that it does not reduce the number of cancer deaths and that therefore it should not be considered an answer to the disease.10

Within this environment of imperfect prevention, detection, and treatment measures, vigorous advocacy in support of the needs of breast cancer patients has emerged. Women began to articulate their discontent with treatments for breast cancer in the early 1970s. As feminists and women's health activists encouraged women to take control of their health care, prominent breast cancer patients, including the feminist Betty Friedan, the journalist Rose Kushner, and the writer Audre Lorde, questioned the need for and the efficacy of the Halsted mastectomy, a radical procedure that had been the primary treatment for the disease for decades and which entailed removal of not only breast tissue but also muscle and part of the chest wall.11 In the 1980s and the 1990s, breast cancer patients, observing the successes of the well-organized and powerful AIDS activist movement, began to mobilize in large numbers, this time with far-reaching social and political goals: to increase public and government attention to their disease as an epidemic that was affecting not only women but also their families and friends. The San Francisco-based organization Breast Cancer Action (BCA), founded in 1990, quickly became quite influential. In 1991, one of BCA's founders, Elenore Pred, became the first breast cancer activist to address the President's Cancer Panel. In 1993, BCA helped draft and enact California's Breast Cancer Act, which raised money for screening and research and guaranteed that advocates would participate in research funding decisions. In 1991, the National Breast Cancer Coalition, a nationwide network made up of survivors, physicians, support groups, and charities and based in Washington, was formed. Its advocacy efforts began in earnest with a letter-writing campaign that led the US Department of Defense to create a $210 million research program devoted to breast cancer research.12 Largely as a result of the NBCC's activities, the US government's funding for breast cancer research increased from approximately $90 million in fiscal year 1990 to more than $800 million by fiscal year 2003. Since then, breast cancer activists have organized a variety of campaigns to increase awareness of the disease, and their efforts have been successful: breast cancer is now the most commonly discussed disease among women.13 It should not be at all surprising, then, that research to find genes linked to breast cancer was highly anticipated and publicized; the genes were simultaneously of scientific, medical, and public interest.

Starting in the 1980s, scientists from the United States, England, France, Germany, Japan, and other countries participated in what was often referred to as an international "race"14 to discover and identify the nucleotide sequences linked to breast cancer, perhaps anticipating that the winner of the race might enjoy both professional and financial rewards. By the early 1990s, discovery of the gene seemed imminent when a group led by Mary-Claire King at the University of California at Berkeley found that Breast Cancer Susceptibility Gene 1 (BRCA1), the first gene linked to breast cancer, lay somewhere on chromosome 17.15 With King's announcement, investigations intensified. Transnational collaborations formed and disintegrated. In September 1994, a group led by scientists at Myriad Genetics (a biotechnology company based in Salt Lake City) and including researchers from the National Institute for Environmental Health Sciences, a subdivision of the National Institutes of Health, announced the mapping and the sequencing of the BRCA1 gene, which seemed to be linked to inherited breast and ovarian cancer.16

The news was met with considerable excitement. The American television network NBC deemed the story so important that it reported the news on September 13, days before the journal article based on the discovery had even completed the formal review process at Science magazine. Tom Brokaw opened his newscast that night by saying: "There's an important breakthrough in breast cancer research. ... A rogue gene could show the way to treatment and prevention." Within hours, other television networks had reported the story, and soon it began to appear on the front pages of newspapers and magazines around the world.17 The New York Times, for example, trumpeted: "Capturing a genetic trophy so ferociously coveted and loudly heralded that it had taken on a near-mythic aura, a collaborative team of researchers has announced the discovery of a gene whose mutation causes hereditary breast cancer."18 The discovery even inspired Harold Varmus, then director of the National Institutes of Health, to state, at a press conference: "This is an extremely important development in the understanding of breast cancer. . . ."19 The extensive media coverage, coupled with Varmus's announcement, underscored how the discovery had been deemed to be of considerable historical, social, and scientific significance.

Notwithstanding the enthusiasm over the BRCA1 gene discovery, many scientists believed that there was at least one more gene linked to breast cancer, and continued their research. In December 1995, investigators led by a group at Britain's Institute for Cancer Research announced that they had mapped and sequenced the BRCA2 gene, which was linked to incidence of ovarian cancer and female and male breast cancer.20 The media announced this second discovery with almost as much excitement as the first. An article in the Financial Times noted: "Scientists at the Institute of Cancer Research in London have won the most competitive race in medical research this year—to isolate the second gene responsible for inherited breast cancer."21 Together, the discoveries of the BRCA1 and BRCA2 genes were seen to lay the foundation for a new era of medicine in which a woman's genetic makeup would guide the prevention and treatment options made available to her.

The BRCA gene discoveries were considered scientifically and medically important because they demonstrated that genes influenced the incidence of common diseases, not only that of rare disorders. Although only 5-10 percent of the individuals who contracted breast cancer did so because of a BRCA mutation, and some wondered if the breast cancers that affected those with BRCA mutations were of a different type (affecting younger people, for example), many hoped that understanding the mechanisms by which the BRCA genes worked would provide insight into all breast cancers. Even if someone had a BRCA gene mutation, however, her future cancer prognosis was not clear. Although research is ongoing, scientists believe that normal BRCA genes act as tumor suppressors, repairing cells that have been damaged through environmental or other means. When a BRCA gene is mutated, a mammary cell is left unable to repair its DNA and is therefore left vulnerable to an assault that could lead to uncontrollable cell growth and eventually a malignant breast tumor. Not only does disease incidence for BRCA mutation-positive individuals involve other, often random factors, but scientists have found hundreds of alterations to these long and complex BRCA genes and each does not necessarily debilitate the gene in the same way or even always leave a cell vulnerable to further DNA damage. It is difficult to discern, then, the exact relationships between individual mutations and risk of future disease. Although little such targeted information is available, studies to date suggest that the lifetime risk of breast cancer for individuals with a BRCA mutation can vary from 36 percent to 85 percent.22

Because the BRCA genes only provided information about disease risk (rather than certainty of future incidence), and because they were linked to a common disease with a high profile, they raised a number of ques-

tions about the use of genetic information for prevention or treatment when they were discovered in the mid 1990s. Would such information have any utility? What would the psychological implications be? Did effective preventive options need to be available to justify availability and use of genetic tests? How should genetic risks be balanced with the risks of medical interventions geared toward prevention? The development of BRCA testing would begin to provide answers to these questions, which would surely condition the continuing emergence of genetic medicine.

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