Breast cancer remains the most common cause of cancer among women in the United States, and it results in more deaths from cancer among women than any other type of cancer, except lung cancer. Over 40,000 women die from breast cancer in the United States each year. A long history of research, now coupled with the new information emerging from the field of molecular genetics, is beginning to explain the basic steps leading to breast cancer, and it will enable the development of novel treatment and prevention strategies.
Almost all breast cancers begin in the glandular structures in the breast that, during lactation, produce milk. These mammary glands are under the control of reproductive hormones that stimulate the monthly cycle of gland expansion and shrinkage, which is a feature of the regular menstrual cycle. Many of the factors associated with the development of breast cancer appear to have their effect through interaction with the hormonal stimulation of these glands.
The risk of developing breast cancer increases throughout a woman's lifetime, and the disease is relatively rare in very young women. The overall association of breast cancer incidence with increasing age may be explained by a model of breast cancer in which a progressive and cumulative series of genetic changes within the cells of the glands is necessary for the initiation of cancer. The longer a woman lives, the more opportunities there are for these genetic changes to accumulate and reach a stage where cells can become cancerous.
One of the most consistent epidemiological observations is the association of reproductive events with risk of breast cancer. Women who have one or more full-term pregnancies have a lower risk for breast cancer, especially if they are pregnant before age twenty. Pregnancy at an early age may help to stabilize the mammary glands and make them less vulnerable to genetic changes later in life. The risk for breast cancer is also significantly decreased among women undergoing surgical removal of the ovaries, particularly if the surgery is performed before age thirty-five. This surgery removes the major source of reproductive hormones and therefore results in less stimulation of the glands in the breast.
Conversely, the greater number of years a woman has regular menstrual cycles, the higher the risk of breast cancer. There is also a modest increase in risk associated with postmenopausal estrogen replacement therapy (especially when used more than 15 years), and with exposure to the synthetic estrogen diethylstilbestrol during pregnancy. Studies have found a significant correlation between breast cancer and levels of hormones—estradiol, estrone, estrone sulfate, prolactin, and dehydroepiandrosterone sulfate. A drug used to treat breast cancer, tamoxifen, blocks estrogen receptors.
Taken together, a significant body of research shows that reproductive hormones—produced internally and taken as medicines—are major determinants of breast cancer risk. Other factors—including genetic predisposition, environmental exposure, and lifestyle choices—may increase cancer risk via hormone regulation.
There are striking racial and ethnic differences in breast cancer incidence and resulting deaths. Overall, rates are highest for Caucasian women and lowest for Native American and Korean women. The general international pattern of breast cancer incidence reveals higher rates for Western, industrialized nations, and lower rates for less industrialized and Asian countries. Even within the United States, there is significant geographic diversity in breast cancer rates, with mortality rates highest in the Northeast and lowest in the South. Much of this variation is thought to be due to regional differences in reproductive events, such as the age when women start having children and their use of hormone medications.
There is also considerable evidence from international comparisons, migration studies, and time trends to support an important role for dietary fat in the causation of breast cancer. However when the diets of specific population groups are followed over time, no definite causal link can be demonstrated. The data on fiber and vitamins and minerals is also contradictory. Dietary studies also show a fairly consistent but weak increase in breast cancer risk with moderate to heavy alcohol consumption. Alcohol may act by stimulating the production of more internal hormones. Among postmenopausal women, body weight has also been positively correlated with both breast cancer incidence and mortality. Although exposure to large amounts of radiation is associated with an increased risk for breast cancer, there does not appear to be any risk associated with routine diagnostic imaging, such as chest X rays and mammograms.
Finally, there is limited data to support a protective role for physical activity, both during leisure time and at work, in terms of breast cancer risk. The effect is most pronounced among premenopausal and younger postmenopausal women. The known association of vigorous physical activity with decreased circulating levels of ovarian hormones may explain this finding, which could have significant public health implications.
Women undergoing breast biopsies whose tissue shows no evidence of cancer, but whose cells have atypical features or faster-than-normal rates of growth have an increased risk of breast cancer, with risks up to eightfold higher in some cases. It is thought that these atypical cells may be a precursor to the development of breast cancer, or they may act as markers for genetic instability within the glandular cells.
Population studies have documented that a history of breast cancer in first-, second-, or third-degree relatives increases cancer risk between twofold and fourfold. Recently two genes, BRCA1 and BRCA2, have, when inherited in a mutated form, been associated with a hereditary form of breast cancer. This form is characterized by early age at onset (5 to 15 years earlier than noninherited cases), cancer in both breasts, and association in the family with tumors of other organs, particularly of the ovary in women and prostate gland in men. Among the normal functions of these genes are the control of the cell cycle and the maintenance of stability of the genes. Both genes are tumor suppressor genes whose proteins help both to control the cell cycle and to repair damaged DNA. Mutations interfere with this vital function, causing damaged cells to reproduce and become cancerous.
The frequency of mutations in BRCA1 in the general population has been estimated to be 1 in 800. Carrier rates are not distributed evenly, however, and mutations tend to concentrate in families with multiple cases of breast or ovarian cancer. Different ethnic groups have unique BRCA1 and BRCA2 mutations. Most notably, three specific mutations are common in Ashkenazic Jews. Additional founder mutations have been described in Sweden and Iceland.
Individuals who have inherited a mutated BRCA1-2 gene face an estimated 36 percent to 85 percent lifetime risk for breast cancer and an estimated 16 percent to 60 percent lifetime risk for ovarian cancer. Among female BRCA1 carriers who have already developed a primary breast cancer, estimates for a second breast cancer in the opposite breast are as high as 64 percent by age seventy. Men who test positive for a mutation in the BRCA2 gene also have a higher lifetime risk for breast cancer.
The identification and location of these breast cancer genes will now permit further investigation of the precise role they play in cancer progression and, specifically, how they interact with reproductive hormones.
Mary B. Daly
Brody, Larry, and Barbara Biesecker. "Breast Cancer Susceptibility Genes BRCA1 and BRCA2." Medicine 77 (1998): 208-226.
Kelsey, Jennifer, and Leslie Bernstein. "Epidemiology and Prevention of Breast Cancer." Annual Review of Public Health 17 (1996): 47-67.
Weber, Barbara L. "Genetic Testing for Breast Cancer." Scientific American Science and Medicine 3, no. 1 (1996): 12-21.
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