Risk factors of breast cancer
Risk factors of breast cancer belongs in the field of epidemiology of breast cancer.
Breast cancer, like other forms of cancer, is considered to result from multiple environmental and hereditary risk factors.
Although many epidemiological risk factors have been identified, the cause of any individual breast cancer is most often unknowable. Epidemiological research informs the patterns of breast cancer incidence across certain populations, but not in a given individual. Approximately 5% of new breast cancers are attributable to hereditary syndromes and well-established risk factors accounted for approximately 30% of cases.
The risk of getting breast cancer increases with age. A woman who lives to age 90 has a lifetime risk of about 14.3%, or one in seven. Despite the fact that they have a proportionately higher risk of breast cancer, there is a lack of significant research on the breast cancer experiences of older women. However, this is beginning to change as studies, such as one published recently in Critical Reviews in Oncology and Hematology, demonstrate that older breast cancer patients experience their illness in a significantly different manner than younger patients. For instance when compared to their younger counterparts, depression was found to occur more often in older breast cancer patients whose advanced age exacerbated the effects of their illness and treatment and resulted in functional impairment. This difference in illness experience highlights the need for more research into the psychosocial support services available to geriatric breast cancer patients.
The probability of breast cancer rises with age, but breast cancer tends to be more aggressive when it occurs in younger people. One type of breast cancer that is especially aggressive and that occurs disproportionately in younger people is inflammatory breast cancer. It is initially staged as Stage IIIb or Stage IV. It also is unique because it often does not present with a lump, so it is often undetected by mammography or ultrasound. It presents with the signs and symptoms of a breast infection like mastitis, and the treatment is usually a combination of surgery, radiation, and chemotherapy.
Men have a lower risk of developing breast cancer (approximately 1.08 per 100,000 men per year), but this risk appears to be rising. Men with gynaecomastia do not have a higher risk of developing breast cancer. There may be an increased incidence of breast cancer in men with prostate cancer. The prognosis, even in stage I cases, is worse in men than in women. The treatment of men with breast cancer is similar to that in older women. Since the male breast tissue is confined to the area directly behind the nipple, treatment for males has usually been a mastectomy with axillary surgery. This may be followed by adjuvant radiotherapy, hormone therapy (such as tamoxifen), or chemotherapy.
United Kingdom being member of International Cancer Genome Consortium is leading efforts to map breast cancer's complete genome.
BRCA1 and BRCA2
In 5% of breast cancer cases, there is a strong inherited familial risk. Two autosomal dominant genes, BRCA1 and BRCA2, account for most of the cases of familial breast cancer. Family members who harbor mutations in these genes have a 60% to 80% risk of developing breast cancer in their lifetimes.Other associated malignancies include ovarian cancer and pancreatic cancer. If a mother or a sister was diagnosed breast cancer, the risk of a hereditary ‘’’BRCA1’’’ or ‘’’BRCA2’’’ gene mutation is about 2-fold higher than those women without a familial history. In addition to the BRCA genes associated with breast cancer, the presence of NBR2, near breast cancer gene 1, has been discovered, and research into its contribution to breast cancer pathogenesis is ongoing.Commercial testing for ‘’’BRCA1’’’ and ‘’’BRCA2’’’ gene mutations has been available since at least 2004.
Hereditary non-BRCA1 and non-BRCA2 breast tumors (and even some sporadic carcinomas) are believed to result from the expression of weakly penetrant but highly prevalent mutations in various genes. For instance, polymorphism has been identified in genes associated to the metabolism of estrogens and/or carcinogens (CYP1A1, CYP1B1, CYP17, CYP19, COMT, NAT2, GSTM1, GSTP1, GSTT, . . . ), to estrogen, androgen and vitamin D action (ESR1, AR, VDR), to co-activation of gene transcription (AIB1), to DNA damage response pathways (CHEK2, HRAS1, XRCC1, XRCC3, XRCC5). Sequence variants of these genes that are relatively common in the population may be associated with a small to moderate increased relative risk for breast cancer. Combinations of such variants could lead to multiplicative effects. Sporadic cancers likely result from the complex interplay between the expression of low penetrance gene(s) (‘‘risk variants’’) and environmental factors. It must be noted, however, that the suspected impact of most of these variants on breast cancer risk should, in most cases, be confirmed in large populations studies. Indeed, low penetrance genes cannot be easily tracked through families, as is true for dominant high-risk genes.
Part of the hereditary non-BRCA1 and non-BRCA2 breast tumors may be associated to rare syndromes, of which breast cancer is only one component. Such syndromes result notably from mutations in TP53 (Li-Fraumeni syndrome), ATM (Ataxia Telangiectasia), STK11/LKB1(Peutz-Jeghers syndrome), PTEN (Cowden syndrome).
RAB11FIP1, TP53, PTEN and rs4973768 are also associated with increased risk of breast cancer. rs6504950 is associated with lower risk of breast cancer.
Mutations in RAD51C confer an increased risk for breast and ovarian cancer.
Alcohol and breast cancer
Alcohol is a risk factor for breast cancer in women.
A woman drinking an average of two units of alcohol per day has 8% higher of developing breast cancer than a woman who drinks an average of one unit of alcohol per day. A study of more than 1,280,000 middle-aged British women concluded that for every additional drink regularly consumed per day, the incidence of breast cancer increases by 11 per 1000. Approximately 6% (between 3.2% and 8.8%) of breast cancers reported in the UK each year could be prevented if drinking was reduced to a very low level (i.e. less than 1 unit/week).
The mechanisms of increased breast cancer risk by alcohol may be:
Increased estrogen and androgen levels
Enhanced mammary gland susceptibility to carcinogenesis.
Increased mammary DNA damage
Greater metastatic potential of breast cancer cells
Dietary influences have been examined since decades with conflicting results and so far failed to confirm any singinficant dependency. One recent study suggests that low-fat diets may significantly decrease the risk of breast cancer as well as the recurrence of breast cancer. Another study showed no contribution of dietary fat intake on the incidence of breast cancer in over 300,000 women. A randomized controlled study of the consequences of a low-fat diet, the Women's Health Initiative, failed to show a statistically significant reduction in breast cancer incidence in the group assigned to a low-fat diet, although the authors did find evidence of a benefit in the subgoup of women who followed the low-fat diet in a strict manner. A prospective cohort study, the Nurses' Health Study II, found increased breast cancer incidence in premenopausal women only, with higher intake of animal fat, but not vegetable fat. Taken as a whole, these results point to a possible association between dietary fat intake and breast cancer incidence, though these interactions are hard to measure in large groups of women.
Specific dietary fatty acids
Although many claims have been made in popular literature there is no solid evidence linking specific fats to breast cancer.
A study published in 2001 found higher levels of monounsaturated fatty acids MUFAs (especially oleic acid) in the erythrocyte membranes of postmenopausal women who developed breast cancer.
That same study discussed that a diet high in MUFAs is not the major determinant of erythrocyte membrane MUFAs, where most oleic acid in mammalian tissue is derived from the saturated stearic acid residue. Where key conversion is controlled by the Delta9-desaturase, which also regulates the transformation of the other common saturated fatty acids (SFAs) (myristic and palmitic). The study discussed that fat content of the diet has an important effect on Delta9-d activity, while high levels of SFAs increase Delta9-d activity by twofold to threefold, whereas polyunsaturated fatty acids (PUFAs) decrease.
That conclusion was partially contradicted by a latter study, which showed a direct relation between very high consumption of omega-6 (PUFAs) and breast cancer in postmenopausal women.
Phytoestrogens#Health Risks and Benefits
Phytoestrogens have been extensively studied in animal and human in-vitro and epidemiological studies. Research failed to establish any noticeable benefit and some phytoestrogens may present a breast cancer risk.
The literature support the following conclusions:
Plant estrogen intake in early adolescence may protect against breast cancer later in life.
The potential risks of isoflavones on breast tissue in women at high risk for breast cancer is still unclear.
Vitamin D#Role in cancer prevention and recovery
Vitamin D is related to reduced risk of breast cancer.
In a study published in the Journal of the American Medical Association, biomedical investigators found that Brassicas vegetable intake (broccoli, cauliflower, cabbage, kale and Brussels sprouts) was inversely related to breast cancer development. The relative risk among women in the highest decile of Brassica vegetable consumption (median, 1.5 servings per day) compared to the lowest decile (virtually no consumption) was 0.58. That is, women who consumed around 1.5 servings of Brassica vegetables per day had 42% less risk of developing breast cancer than those who consumed virtually none.
A significant environmental effect is likely responsible for the different rates of breast cancer incidence between countries with different dietary customs. Researchers have long measured that breast cancer rates in an immigrant population soon come to resemble the rates of the host country after a few generations. The reason for this is speculated to be immigrant uptake of the host country diet. The prototypical example of this phenomenon is the changing rate of breast cancer after the arrival of Japanese immigrants to America.
In 2009, a case-control study of the eating habits of 2,018 women suggested that women who consumed mushrooms had an approximately 50% lower incidence of breast cancer. Women who consumed mushrooms and green tea had a 90% lower incidence of breast cancer. A case control study of 362 Korean women also reported an association between mushroom consumption and decreased risk of breast cancer.
Gaining weight after menopause can increase a woman's risk. A recent study found that putting on 9.9 kg (22 lbs) after menopause increased the risk of developing breast cancer by 18%.
Persistently increased blood levels of estrogen are associated with an increased risk of breast cancer, as are increased levels of the androgens androstenedione and testosterone (which can be directly converted by aromatase to the estrogens estrone and estradiol, respectively). Increased blood levels of progesterone are associated with a decreased risk of breast cancer in premenopausal women. A number of circumstances which increase exposure to endogenous estrogens including not having children, delaying first childbirth, not breastfeeding, early menarche (the first menstrual period) and late menopause are suspected of increasing lifetime risk for developing breast cancer.
However, not only sex hormones, but also insulin levels are positively associated with the risk of breast cancer.
Pregnancy, childbearing and breastfeeding
Lower age of first childbirth, compared to the average age of 24, having more children (about 7% lowered risk per child), and breastfeeding (4.3% per breastfeeding year, with an average relative risk around 0.7) have all been correlated to lowered breast cancer risk in large studies.In contrast, for instance, having the first live birth after age 30 doubles the risk compared to having first live birth at age less than 25. Never having children triples the risk.
Hormonal contraceptives may produce a slight increase in the risk of breast cancer diagnosis among current and recent users, but this appears to be a short-term effect. In 1996 the largest collaborative reanalysis of individual data on over 150,000 women in 54 studies of breast cancer found a relative risk (RR) of 1.24 of breast cancer diagnosis among current combined oral contraceptive pill users; 10 or more years after stopping, no difference was seen. Further, the cancers diagnosed in women who had ever used hormonal contraceptives were less advanced than those in nonusers, raising the possibility that the small excess among users was due to increased detection. The relative risk of breast cancer diagnosis associated with current and recent use of hormonal contraceptives did not appear to vary with family history of breast cancer.
Hormone replacement therapy
Data exist from both observational and randomized clinical trials regarding the association between postmenopausal Hormone replacement therapy (menopause) (HRT) and breast cancer. The largest meta-analysis (1997) of data from 51 observational studies, indicated a relative risk of breast cancer of 1.35 for women who had used HRT for 5 or more years after menopause. The estrogen-plus-progestin arm of the Women's Health Initiative (WHI), a randomized controlled trial, which randomized more than 16,000 postmenopausal women to receive combined hormone therapy or placebo, was halted early (2002) because health risks exceeded benefits. One of the adverse outcomes prompting closure was a significant increase in both total and invasive breast cancers (RR = 1.24) in women randomized to receive estrogen and progestin for an average of 5 years. HRT-related breast cancers had adverse prognostic characteristics (more advanced stages and larger tumors) compared with cancers occurring in the placebo group, and HRT was also associated with a substantial increase in abnormal mammograms. Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk.
Oophorectomy and mastectomy
Prophylactic oophorectomy (removal of ovaries) and mastectomy in individuals with high-risk mutations of BRCA1 or BRCA2 genes reduces the risk of developing breast cancer as well as reducing the risk of developing ovarian cancer. Because of a complex balance of benefits and risks of a prophylactic surgery it is recommended only in very specific cases.
Hormonal therapy (oncology)
Hormonal therapy has been used for chemoprevention in individuals at high risk for breast cancer. Overall it is recommended only in very special circumstances. In 2002, a clinical practice guideline by the US Preventive Services Task Force (USPSTF) recommended that "clinicians discuss chemoprevention with women at high risk for breast cancer and at low risk for adverse effects of chemoprevention" with a grade B recommendation.
Selective estrogen receptor modulators (SERMs)
The guidelines were based on studies of SERMs from the MORE, BCPT P-1, and Italian trials. In the MORE trial, the relative risk reduction for raloxifene was 76%. The P-1 preventative study demonstrated that tamoxifen can prevent breast cancer in high-risk individuals. The relative risk reduction was up to 50% of new breast cancers, though the cancers prevented were more likely estrogen-receptor positive (this is analogous to the effect of finasteride on the prevention of prostate cancer, in which only low-grade prostate cancers were prevented). The Italian trial showed benefit from tamoxifen.
Additional randomized controlled trials have been published since the guidelines. The IBIS trial found benefit from tamoxifen. In 2006, the NSABP STAR trial demonstrated that raloxifene had equal efficacy in preventing breast cancer compared with tamoxifen, but that there were fewer side effects with raloxifene. The RUTH Trial concluded that "benefits of raloxifene in reducing the risks of invasive breast cancer and vertebral fracture should be weighed against the increased risks of venous thromboembolism and fatal stroke". On September 14, 2007, the US Food and Drug Administration approved raloxifene (Evista) to prevent invasive breast cancer in postmenopausal women.
Many xenoestrogens (industrially made estrogenic compounds) and other endocrine disruptors are potential risk factors of breast cancer.
Diethylstilbestrol (DES) is a synthetic form of estrogen. It has been used between the early 1940s and 1971. Pregnant women took DES to prevent certain pregnancy complications. However, it also increased their risk of breast cancer. It also increased the risk of breast cancer in the prenatally exposed daughters after they have reached an age 40 years.
Furthermore, there is exposure to endocrine disruptors from the environment, in addition to phytoestrogens mentioned above in the diet section. See xenoestrogens in environmental factors below
According to a review, the main mechanisms by which environmental compounds increase breast cancer risk are acting like hormones, especially estrogen, or affecting susceptibility to carcinogenesis. The evidence to date generally supports an association between breast cancer and polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs). Dioxins and organic solvents, on the other hand, have only shown an association in sparse and methodologically limited studies, but are suggestive of an association. Overall, however, evidence is still based on a relatively small number of studies.
Many xenoestrogens (industrially made estrogenic compounds) are endocrine disruptors, and potential risk factors of breast cancer.
A substantial and growing body of evidence indicates that exposures to certain toxic chemicals and hormone-mimicking compounds including chemicals used in pesticides, cosmetics and cleaning products contribute to the development of breast cancer.
The increasing prevalence of these substances in the environment may explain the increasing incidence of breast cancer, though direct evidence is sparse.
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Bisphenol A (BPA) is a common Xenoestrogen chemical found in plastics, such as bottles, PVC pipes and in the coating of food cans. Research on mice and women has shown that exposure Bisphenol A during development has carcinogenic effects and produces precursors of breast cancer. Recent research has shown evidence that BPA remains more time in the body than previously thought.
Consumer groups recommend that people wishing to lower their exposure to bisphenol A avoid canned food and polycarbonate plastic containers (which shares resin identification code 7 with many other plastics) unless the packaging indicates the plastic is bisphenol A-free. The National Toxicology Panel recommends avoiding microwaving food in plastic containers, putting plastics in the dishwasher, or using harsh detergents on plastics, to avoid leaching.
Aromatic amines are chemicals that are produced when products such as dyes, polyurethane products, and certain pesticides are made. They are also found in cigarette smoke, fuel exhaust, and in over cooked, burned meat. The three types of aromatic amines monocyclic, polycyclic, and heterocyclic have all been found in recent studies of breast health. Monocyclic amines have been found to cause mammary cancer in rats. Studies have shown that women who eat higher amounts of overcooked meat, meaning more exposure to heterocyclic amines, have also been diagnosed with more post-menopausal breast cancer. Heterocyclic amines also have the ability to copy estrogen and in laboratory studies have been found to encourage the growth of cancerous tumors on human tissue.
Benzene is a very popular petrochemical solvent. Benzene exposure mostly originates from air pollution resulting from industrial burning, exhaust and gas fumes, as well as cigarette smoke. Benzene can also be found in some nail polishes, as well as some nail polish removers. The International Agency for Research on Cancer and the National Toxicology Program have labeled benzene as a definite human carcinogen. Multiple studies point to a correlation between benzene exposure and breast cancer risk. Laboratory studies on mice have shown that a high level of benzene exposure can lead to mammary cancer.
Although the pesticide DDT was banned over 20 years ago, studies have shown that there are still trace amounts found in certain agricultural products, as well as in human and animal milk. While individual studies have come to conflicting conclusions, the most recent reviews of all the evidence conclude that exposure to DDT before puberty increases the risk of breast cancer later in life.
Ethylene oxide is a chemical that can be found in some personal care products, mainly in the form of fragrance. It is also used for the sterilization of various medical objects. The National Toxicology Program has labeled ethylene oxide as a definite human and animal carcinogen. A study done by the National Institute for Occupational Safety and Health including 7,576 women found a direct correlation between breast cancer rates and exposure to ethylene oxide during medical sterilization processes. Also, human breast cells put into contact with small amounts of ethylene oxide in a laboratory can lead to DNA damage of the breast tissue.
Polycyclic aromatic hydrocarbons
Polycyclic aromatic hydrocarbons are chemical products of combustion from coal burners, fuel, cigarette smoke, and various other sources. PAH's are often found in the air and are breathed into the body. PAH's bioaccumulate easily and can copy the estrogen hormone. PAH's can also be genotoxic, meaning they have the ability to harm DNA.
Red No. 3
Red No. 3 is a coloring agent used in some foods. In laboratory tests human breast cell DNA was found positive for damage when put into contact with Red No. 3, which means that it is genotoxic.
Vinyl chloride is produced when PVC or polyvinly chloride is made. PVC is found in plastic packaging, outerwear, plastic toys and other plastic products. Vinyl chloride can be found in cigarette smoke and the air around garbage and land fills. It can also be found in the wastewater when PVC is made. The National Toxicology Program and the International Agency for Research on Cancer have both labeled vinyl chloride as a definite human carcinogen.
Until recently, most studies had not found an increased risk of breast cancer from active tobacco smoking. Beginning in the mid-1990s, a number of studies suggested an increased risk of breast cancer in both active smokers and those exposed to secondhand smoke compared to women who reported no exposure to secondhand smoke. By 2005 enough evidence had accumulated for the [California Environmental Protection Agency] to conclude that breathing secondhand smoke causes breast cancer in younger, primarily premenopausal women. The Agency concluded that the risk was increased by 70%, based on epidemiological studies and the fact that there are many mammary carcinogens in secondhand smoke. The following year (2006) the US Surgeon General identified the same risk increase and concluded that the evidence is "suggestive," one step below causal. There is some evidence that exposure to tobacco smoke is most problematic between puberty and first childbirth. The reason is that breast tissue appears most sensitive to chemical carcinogens breast cells not fully differentiated until lactation. The likely reason that the older studies of active smoking did not detect risks associated with smoking was that they compared active smokers to all nonsmokers (which includes many passive smokers). The newer studies, which exclude passive smokers from the control group, generally show elevated risks associated with active as well as passive smoking.
Breathing secondhand smoke increases breast cancer risk by 70% in younger, primarily pre-menopausal women. The California Environmental Protection Agency has concluded that passive smoking causes breast cancer and the US Surgeon General has concluded that the evidence is "suggestive," one step below causal. There is some evidence that exposure to tobacco smoke is most problematic between puberty and first childbirth. The reason that breast tissue appears most sensitive to chemical carcinogens in this phase is that breast cells are not fully differentiated until lactation.
Women who have received high-dose ionizing radiation to the chest (for example, as treatments for other cancers) have a relative risk of breast cancer between 2.1 to 4.0. The risk increases with increased dose. In addition, the risk is higher in women irradiated before age 30, when there is still breast development.
Dioxins (most notably the polychlorinated dibenzodioxins) are chemicals that are produced when chlorinated products are burned, such as polyvinyl chloride (PVC). This occurs when chlorinated products are used in certain manufacturing industries. Dioxins are also added to the air when gasoline and diesel fuels break down. Dioxins are able to bioaccumulate, meaning that they settle and stay in human and animal fat for long periods of time. There are many different types of dioxins and only a few of them have been labeled by the Environmental Protection Agency as definite human carcinogens and endocrine hormone disruptors. Although dioxins are floating in the air, they eventually settle on plants and other vegetation surfaces. These plants and vegetation are them eaten by cows and other animals. Humans end up eating the produce, milk, eggs, and meat produced by these animals that have consumed dioxin covered vegetation. Dioxins are more harmful when ingested this way. Multiple studies have led to the idea that increased dioxin levels can increase one's risk for breast cancer. A study done in 1976 after a chemical plant explosion in Seveso, Italy concluded that high dioxin level exposure in a woman's body correlated with a more than double chance of developing breast cancer.
Light at night and disturbance of circadian rhythm
In 1978 Cohen et al. proposed that reduced production of the hormone melatonin might increase the risk of breast cancer and citing "environmental lighting" as a possible causal factor. Researchers at the National Cancer Institute (NCI) and National Institute of Environmental Health Sciences conducted a study in 2005 that suggests that artificial light during the night can be a factor for breast cancer by disrupting melatonin levels.
In 2007, "shiftwork that involves circadian disruption" was listed as a probable carcinogen by the World Health Organization's International Agency for Research on Cancer. (IARC Press release No. 180). Multiple studies have documented a link between night shift work and the increased incidence of breast cancer. A review of current knowledge of the health consequences of exposure to artificial light at night including the increased incidence of breast cancer and an explanation of the causal mechanisms has been published in the Journal of Pineal Research in 2007.
The protective effects of iodine on breast cancer have been postulated from epidemiologic evidence and described in animal models.
Factors with inconclusive research
One research published in 2009 has show that moderate green or black tea consumption (three or more cups per day) can reduce breast cancer risk by 37% in women younger than 50 years old, comparing with women who drank no tea at all. But no association was found for overall women. However that study has been criticized for inaccuracy and another study found no substantial association between and tea consumption in the overall, but found a weak inverse association between caffeine-containing beverages and risk of postmenopausal breast cancer.
Specifically about green tea, one study has found significant inverse association between risk of breast cancer and green tea intake in Asian women who were low soy consumers.
1,3-Butadiene is an environmental factor that can be found in air pollution and can be produced by combustion engines, as well as petroleum refineries. It is found in cigarette smoke and is also used in the making and processing of certain synthetic rubber products and fungicides. The National Toxicology Program has labeled 1,3-Butadiene as definite human carcinogen. The EPA has stated that people are mainly put in contact with this chemical through the means of simple inhalation.
Mammographic Density is a breast cancer risk factor under study.
Factors with minimal or no impact on risk.
Abortion-breast cancer hypothesis
The abortion-breast cancer (ABC) hypothesis (supporters call it the abortion-breast cancer link) posits induced abortion increases the risk of developing breast cancer; it is a controversial subject and the current scientific consensus has concluded there is no significant association between first-trimester abortion and breast cancer risk.
Bras and tight fitting clothing have not been found to be related to breast cancer.
Much has been made of the possible contribution of aluminum-containing underarm antiperspirants to the incidence of breast cancer, since the most common location of a breast cancer is the upper outer quadrant of the breast. Aluminum salts, such as those used in anti-perspirants, have recently been classified as metalloestrogens. In research published in the Journal of Applied Toxicology, Dr. Philippa D. Darbre of the University of Reading has shown that aluminum salts increase estrogen-related gene expression in human breast cancer cells grown in the laboratory. Fortunately, this in-vitro association between aluminum salts and estrogen activity does not translate into an increased risk of breast cancer in humans. The lack of association between underarm deodorants and breast cancer has been the subject of a number of research articles.
There is no persuasive connection between fertility medications and breast cancer.
The results of the studies about the influence of dietary folic acid on breast cancer have been contradictory.
Humans are not the only mammals susceptible to breast cancer. Some strains of mice, namely the house mouse (Mus domesticus) are prone to breast cancer which is caused by infection with the mouse mammary tumour virus (MMTV or "Bittner virus" for its discoverer Hans Bittner), by random insertional mutagenesis. This finding is taken to mean that a viral origin of human breast cancer is at least possible, though there is no definitive evidence to support the claim that MMTV causes human breast cancer. For example, there may be critical differences between cancer pathogenesis in mice and people. The understanding of the role of MMTV or other viruses in human breast cancer is preliminary as of May 2010