Learn about the BRCA1 and BRCA2 genes including a number of key genetic variants associated with several cancer types.
What Is Cancer?
Cancer is a complex group of diseases that cause considerable illness and can often be deadly. There were 18 million new cancer cases and 9.5 million deaths worldwide in 2018 alone, making it one of the most common severe diseases [1].
Cancer occurs when the factors responsible for regulating the growth and development of cells become damaged or dysregulated, which can cause the body’s cells to start growing and dividing uncontrollably. Over time, this uncontrolled growth leads to the formation of lumps of cancerous cells — commonly known as “tumors” — which continue to grow, and which can eventually damage other nearby tissues, or interfere with the functioning of the body’s organs.
Additionally, cancerous cells can sometimes “break away” from the initial tumor and spread (“metastasize”) to other parts of the body, causing the cancer to spread even further throughout the body.
The risk of developing cancer is generally determined by a combination of genetic and environmental factors. The genetic side of this equation typically depends on what kind of information a person’s DNA contains; and because every person’s DNA is different, so is their relative chance of developing cancer at some point in their lives. On the other side of the equation, some of the environmental factors that can influence a person’s risk of cancer include their age, lifestyle, and diet, their personal medical and disease history, and their degree of exposure to certain toxic chemicals or types of radiation.
Mechanisms of Cancer Development and Prevention
Damage to a cell’s DNA — such as from oxidative stress, toxins, or radiation — can lead to mutations and other critical alterations in the cell’s chromosomes. Such genetic mutations are widely recognized as one of the key biological events that can trigger the formation of cancer cells and tumors [2].
Fortunately, the body possesses a number of “defense mechanisms” that can repair DNA damage before it causes cells to turn cancerous [2]. Among them, BRCA1 and BRCA2 are two of the best-known “tumor suppressor” genes. This pair of genes encodes two important proteins that can help prevent the development of cancer through several different mechanisms, including repairing DNA damage, controlling the “cell cycle,” and regulating the expression of various other genes throughout the body. However, certain variations in these genes have been associated with increased risk of several different types of cancer — especially breast cancer, ovarian cancer, and prostate cancer [3, 4].
What Are The BRCA1 and BRCA2 Genes?
The BRCA1 and BRCA2 genes, short for ‘breast cancer susceptibility’, code for the BRCA1 and BRCA2 proteins. The BRCA1 and BRCA2 proteins are produced in most tissues throughout the body, and play key roles in repairing DNA damage, controlling the “cell cycle,” and regulating the expression of a wide variety of other genes [4, 3].
Because these genes and their proteins play such diverse and important roles throughout the body, BRCA1 and BRCA2 effectively function as “tumor suppressor” genes. However, mutations in certain regions of these genes may predispose some people to different types of cancer [5, 3].
The Roles of BRCA Proteins
1) Maintaining DNA Stability
The genome inside all living cells is frequently exposed to damaging agents such as byproducts of cellular metabolism (e.g., free radicals), ionizing radiation (e.g., UV radiation from the sun), and certain chemicals and toxins (such as cigarette smoke and other drugs).
The simultaneous breakage of both DNA strands — what biologists often call a “double-strand break” — is a particularly troublesome type of DNA damage because it can cause chromosome rearrangements if the strands are improperly rejoined. This may kill the cell or turn it into a cancer cell if the rearrangement is left unrepaired [6].
Both BRCA1 and BRCA2 play key roles in repairing double-strand breaks:
- BRCA1 interacts with protein complexes that locate DNA damage, and which then activate pathways that restore the original organization of the chromosome. Importantly, BRCA1 also helps direct BRCA2 to damaged sites [7, 8].
- BRCA2 recruits a key recombination enzyme (RAD51), which properly rejoins the DNA strands. In addition, it also helps correct any stray chromosomal abnormalities that may arise accidentally during the normal replication of DNA when the body’s cells divide and reproduce [9, 10].
2) Stopping The Cell Cycle
The cell cycle is the process by which a cell grows and divides into two identical daughter cells. A key step to this cycle is DNA replication, in which cellular DNA is used as a template to produce a new copy so that both daughter cells carry the whole genome.
In response to DNA damage, BRCA1 activates genes and proteins that stop the cell cycle at several stages called ‘checkpoints’. This allows the repair of mutations before cell division, thus preventing their transmission to the newly-formed cells [11, 12, 13, 14].
Although less widely-investigated, BRCA2 is also involved in the regulation of cell cycle progression by stopping this process before DNA replication [15, 16].
3) Regulating Gene Expression and Protein Activity
BRCA1 stimulates gene expression by targeting activating proteins to specific DNA regions. Its activity is markedly reduced in several mutated variants associated with breast and ovarian cancer [17, 18].
Similarly, BRCA2 interacts with proteins that control the expression of genes involved in cancer progression and regulates their activity [19, 20].
BRCA1 can also regulate gene expression epigenetically. Mutated BRCA1 variants in which these mechanisms don’t work have been associated with some cancer types [21, 22, 23, 24].
Moreover, BRCA1 can modify the stability, activity, and location of multiple proteins, including those involved in cancer progression, by adding a small protein tag called ubiquitin. BRCA1 mutations in a region required for this process may predispose to cancer development [25, 26].
4) Reducing Oxidative Stress
Free radicals are naturally formed as byproducts of cellular metabolism and act as messenger molecules. However, free radicals in excess cause oxidative stress that damages components such as fats, proteins, and DNA. This contributes to aging and several diseases, including cancer [27, 28].
In cell-based studies, BRCA1 overproduction reduced the levels of free radicals while its absence increased them [29, 30].
In line with this, engineered mice lacking BRCA1 produced more free radicals and had higher cancer rates in the esophagus and stomach in response to a cancer-causing chemical [31].
BRCA Proteins and Cancer
Breast and Ovarian Cancer
Mutations in the BRCA1 and BRCA2 genes were first associated with breast and ovarian cancer in the 1990s. Hundreds of different mutations have been identified so far and account for over 20% of hereditary breast and ovarian cancers. Most of them result in a total absence of these proteins or the production of inactive versions [32, 33, 34, 35].
Risk BRCA1 and BRCA2 mutations are especially frequent in certain populations such as Ashkenazi Jews and Icelanders, as well as in rare types of breast cancer such as those occurring in men or in women younger than 30 years old [36, 37].
BRCA1 and BRCA2 mutations seem to cause cancer primarily in the breasts and ovaries due to the complex interaction of these genes with the levels and activity of the sex hormones estrogen and progesterone [38, 39, 40, 41, 42].
While 1 out of 8 (12.5%) women develop breast cancer over their lifetime, carrying a BRCA1 mutation increases this risk to 20% at 40 years of age, 51% at 50, and 84% after 70. In turn, those with a mutated BRCA2 variant bear a risk of 28% at 50 and 85% after 70 [43, 44].
BRCA1 mutations cause more aggressive breast cancers that are usually detected at later stages and don’t respond to hormone therapy because they lack estrogen and progesterone receptors (they are triple negative). Conversely, those caused by BRCA2 mutations are more similar to non-hereditary cancers and usually express estrogen receptors [45, 46].
The lifelong risk of ovarian cancer increases from 1-2% to 40-50% in women with BRCA1 mutations and to 28% for those with BRCA2 mutations [43, 47].
Prostate Cancer
Prostate cancer is the second most common tumor in men worldwide. With over 50% of cases occurring in people with a family history, it’s the common cancer with the strongest genetic component [48, 49].
Although BRCA mutations are only found in approximately 2% of prostate cancer patients, they are the most well-known cause of hereditary prostate cancer. BRCA1 mutations increase the risk of prostate cancer by almost 4-fold, while men carrying a BRCA2 mutation may have a 4- to 8-fold higher risk [50, 51, 52].
BRCA mutations are associated with earlier-onset, more aggressive prostate cancers with a poorer prognosis [53, 54].
Other Cancer Types
Some BRCA1 and BRCA2 mutations and variants may also increase the risk of other cancer types such as:
- Pancreatic [55]
- Skin (melanoma) [56]
- Colon [57]
- Lymph node [58]
- Cervical [59]
- Esophageal [60]
- Lung [61]
- Urinary tract [62]
- Brain [63]
- Thyroid [64]
- Head and Neck [65]
- Leukemia [66]
Recommendations
Below is a list of lifestyle and dietary recommendations that may optimize your overall health. They are all broadly relevant to cancer mechanisms associated with both BRCA1 and BRCA2. As always, we strongly encourage you to discuss any potential lifestyle changes or new supplements with your doctor first, in order to avoid any potential negative interactions.
Note: In a few cases, the effectiveness of a recommendation may depend on some of the specific genotypes you personally carry in one of the two BRCA genes — or, in some cases, even on your genotype for one single specific SNP! Therefore, you may want to look up what your genotype is for a particular SNP when deciding how best to prioritize the different recommendations discussed below.
1) Cruciferous Vegetables
Cruciferous vegetables such as broccoli, cabbage, cauliflower, kale, and Brussels sprouts are rich in a class of sulfur-containing compounds called glucosinolates. Eating and digesting them transforms glucosinolates into compounds with anticancer activity such as sulforaphane, indole-3-carbinol (I3C), diindolylmethane (DIM), and benzyl isothiocyanate [67, 68, 69].
Eating a diet rich in cruciferous vegetables has been associated with lower rates of breast, ovarian, and prostate cancer, and with a better outcome of these diseases [70, 71, 72, 73, 74, 75, 76].
In a clinical trial on women with BRCA mutations, supplementation with DIM for one year helped prevent breast cancer by reducing breast density. In breast and prostate cancer cells, its precursor I3C increased BRCA1 and BRCA2 expression [77, 78].
2) Plant Phytoestrogens (Soy, Flax, Red Clover)
Phytoestrogens are plant-derived substances that resemble the sex hormone estrogen. When consumed with the diet, phytoestrogens can bind to estrogen receptors and either mimic or block the effects of this hormone. Additionally, they build up in the tissues and can be toxic to cancer cells.
Soy is rich in a class of phytoestrogens called isoflavones. Multiple studies have associated eating a diet rich in soy with a reduced incidence of breast, ovarian, and prostate cancer. However, most studies were done only in Asian populations and those including other ethnicities had more modest results [79, 80, 81, 82, 83, 84, 85, 86, 87].
Importantly, the protective effect was also observed in carriers of BRCA mutations, especially in the BRCA2 gene, in a Korean study. In breast cancer cells, the soy isoflavone genistein promoted the expression of both BRCA1 and BRCA2 [88, 89, 78].
Flaxseed contains another type of phytoestrogens called lignans. Multiple studies found that dietary flaxseed can help prevent breast cancer, especially in postmenopausal women, and increase the survival of breast cancer patients [90, 91].
Preliminary research in humans and mice suggests that dietary flaxseed reduces the growth of prostate tumors [92, 93, 94, 95].
Its effects on ovarian cancer haven’t been investigated in humans, but flaxseed and its active compounds prevented it in hens and killed ovarian cancer cells in test tubes [96, 97, 98].
3) Dietary Flavonoids (Green Tea, Fruits, Vegetables)
Flavonoids are phenolic compounds naturally found in plants. Owing to their antioxidant activity, these compounds have been widely investigated concerning their role in preventing chronic conditions such as heart disease and cancer.
Green tea is produced by exposing fresh leaves to heat or hot steam immediately after plucking, which results in minimal breakdown of its antioxidant flavonoids. The most abundant flavonoid in green tea is epigallocatechin gallate (EGCG) [99].
High intake of green tea showed a protective effect against the incidence and recurrence of breast, ovarian, and prostate cancer in multiple studies. Again, more studies in non-Asian populations are needed to determine if this effect is dependent on the race [100, 101, 102, 103, 104, 105].
Unfortunately, the specific effects of green tea on carriers of BRCA mutations haven’t been investigated. A cell-based study found that its polyphenol epigallocatechin gallate reduced the growth of breast cancer cells and helped maintain BRCA1 expression [89].
Several studies have evaluated the effects of other dietary flavonoids commonly found in fruits and vegetables on health outcomes. Among the different classes, flavonols (quercetin, kaempferol, and myricetin) were most effective at preventing both breast and ovarian cancer, while flavones (apigenin and luteolin) only reduced breast cancer risk [106, 107, 108, 109, 110, 111, 112].
In the case of prostate cancer, preliminary research in animals and cells showed promising results for different flavonoids but the evidence from human studies is mixed [113, 114, 115].
The toxic effects of quercetin on cancer cells have been most widely investigated. Interestingly, breast cancer cells with BRCA2 mutations were three times more sensitive to this flavonoid. Food sources of quercetin include onions, berries, apples, and green leafy vegetables [116, 117].
4) Dietary Carotenoids (Tomatoes, Sweet potatoes, Carrots, Pumpkin)
Carotenoids are red, orange, and yellow pigments naturally found in plants. They give their fruits, flowers, roots, and tubers their characteristic colors and act as antioxidants when consumed with the diet.
Beta-carotene is an orange carotenoid found in fruits and vegetables such as carrots, pumpkins, sweet potatoes, mangoes, papayas, and cantaloupes. Once absorbed in the gut, beta-carotene is transformed into vitamin A [118].
Lycopene is a bright red carotenoid especially found in fruits and vegetables such as tomatoes, watermelons, carrots, grapefruits, and papayas. As opposed to beta-carotene, lycopene doesn’t have pro-vitamin A activity [119].
High blood levels of these and other carotenoids have been consistently associated with a reduced risk of breast cancer [120, 121].
Similarly, eating a diet rich in tomatoes and other lycopene sources is a well-known protective factor against prostate cancer. The effect is enhanced if the tomatoes are cooked, which increases lycopene absorption [122, 123, 124, 125].
The results are more mixed in the case of ovarian cancer. Most studies associated high intake of dietary carotenoids with a reduced risk of ovarian cancer, but some failed to find this association [126, 127, 128, 129, 130, 131, 132].
In a clinical trial, a synthetic carotenoid (fenretinide) reduced the incidence of ovarian cancer. Fenretinide was especially effective in carriers of BRCA mutations. In a cell-based study, fenretinide reduced the expression of mutated BRCA genes [133, 134].
Importantly, smokers should stick to food doses of beta-carotene. In several studies on smokers, long-term supplementation with high doses of this carotenoid was associated with an increased risk of lung cancer [135, 136].
5) Reducing Alcohol Intake
Alcohol is a well-known risk factor for breast cancer, especially in women drinking 2 or more servings per day. Alcohol can act through both estrogen-dependent and independent pathways and thus cause estrogen receptor-positive and -negative tumors [137]:
- Alcohol elevates blood estrogen levels, thus stimulating cell proliferation [138, 139].
- Alcohol is broken down to acetaldehyde, which increases oxidative stress and the risk of chromosome aberrations [140].
Conversely, alcohol is not associated with ovarian cancer. In the case of prostate cancer, the results are mixed but evidence suggests alcohol may be associated with a worse progression rather than with an increased incidence [141, 142, 143, 144, 145].
Importantly, acetaldehyde reduces BRCA2 levels by triggering its breakdown. This means that carriers of BRCA2 mutations may be more susceptible to the cancer-causing effects of alcohol [146].
6) Avoiding Cigarette Smoke
Both active and second-hand exposure to cigarette smoke are clearly associated with breast cancer incidence. In women with this disease, smoking predicts a reduced survival [147, 148, 149, 150].
Smoking has also been associated with an increased incidence, aggressivity, recurrence, and mortality of prostate cancer [151, 152, 153, 154].
Depending on the type of ovarian tumors, smoking can promote or prevent their development. Overall, it causes a slight reduction in ovarian cancer risk. However, its combination with excess weight and physical inactivity reduces survival in ovarian cancer patients [155, 156, 157].
Several studies found that cigarette smoking further increased the risk of breast cancer in carriers of BRCA mutations, especially BRCA2. Similarly, the minor variant ‘T’ of the BRCA2 rs11571833 polymorphism further increased the incidence of head and neck cancer in smokers [158, 159, 160, 161, 65].
7) Physical Exercise/Maintaining a Healthy Weight
Physical activity is clearly associated with a reduced risk of breast cancer. Exercise is similarly effective in carriers and non-carriers of BRCA mutations [162, 163, 164, 165, 166, 167].
In contrast, exercise is only weakly associated with ovarian cancer and doesn’t seem to influence the risk of prostate cancer [168, 169, 170, 171, 172, 173].
Importantly, exercise helps maintain a healthy weight. Excess weight increases the risk of these three cancer types, while weight loss reduces it. Losing weight, especially during young adulthood, is similarly effective to prevent breast and ovarian cancer in both carriers and non-carriers of BRCA mutations [162, 174, 175, 176, 177].
8) Maintaining a Regular Sleeping Schedule
Disrupting the circadian rhythm is associated with cancer, possibly because it causes alterations in the expression of genes that regulate tumor development [178].
The effect has been most widely investigated in the case of breast cancer. Most studies associated circadian disruption caused by shift work with an increased incidence and worse prognosis of this cancer type [179, 180, 181, 182].
Shift work has also been associated with prostate cancer, although less strongly. One meta-analysis concluded that the effect may be restricted to workers of rotating shifts as opposed to those doing fixed night-shift work [183, 184].
Importantly, a study found that shift work reduces the expression of both BRCA1 and BRCA2. This may contribute to cancer onset by reducing DNA repair [185].
People with risk BRCA variants should try to maintain regular sleeping hours. If you struggle to do so or have to work in shifts, you can take melatonin. This supplement helps regulate the circadian rhythm and some preliminary research suggests its potential activity against breast, prostate, and colorectal cancer [186, 187].
9) Moderate Sun Exposure
Getting regular, moderate sun exposure is a safe way to maintain normal vitamin D levels because UV radiation stimulates its production. This vitamin helps build strong bones and support immune balance [188].
Vitamin D deficiency has been associated with an increased risk of breast cancer in premenopausal women. It also predicted increased risk of recurrence and death in breast cancer patients [189, 190, 191, 192, 193, 194].
In a study of 40 women with breast cancer, those carrying a BRCA2 mutation had higher blood vitamin D levels. The tumors in this group were smaller and more differentiated, which is associated with a better outcome [195].
Cell-based studies strongly suggest that vitamin D prevents ovarian cancer. Some human studies associated high blood levels of this vitamin with reduced incidence and increased survival, but the evidence is weak and inconsistent. Indeed, the most recent meta-analysis concluded that vitamin D has no effect on this cancer type [196, 197, 198, 199, 200, 201].
The evidence doesn’t support a role for vitamin D in preventing prostate cancer either. One meta-analysis even found that high vitamin D levels increased the risk [202, 203, 204, 205, 206].
10) Reducing Exposure to Toxic Chemicals
Occupational exposure to different chemicals such as organic solvents, volatile organic compounds (VOC), and fuel combustion byproducts has been consistently associated with different cancer types. These chemicals cause DNA damage that may trigger tumor development [207, 208, 209, 210, 211, 212, 213].
In a study of men with BRCA mutations who developed breast cancer, truck driving was the most frequent occupation. The authors of the study speculated that the constant exposure to polycyclic aromatic hydrocarbons may have increased their cancer risk [214].
The minor ‘C’ variant of the BRCA2 rs144848 polymorphism is associated with lower DNA damage in people exposed to chromium and a reduced incidence of non-Hodgkin lymphoma in those exposed to benzene. However, this variant increased the risk of non-Hodgkin lymphoma in people exposed to cancer-causing components from hair dyes [215, 216, 217].
People working with or exposed to potential cancer-causing chemicals should reduce their exposure as much as possible by wearing protective equipment and following safety guidelines, especially if they carry a risk BRCA variant.
VOCs can be elevated from new furniture or paints and can be a problem indoors if the windows are closed. Always make sure to open the windows and get as much fresh air as possible.
11) Omega-3 Fatty Acids
Omega-3 fatty acids are polyunsaturated fatty acids that reduce inflammation and help prevent conditions such as heart disease, cancer, and osteoporosis.
Fatty fish such as salmon, sardines, mackerel, and tuna are especially rich in EPA and DHA acid. The main omega-3 fatty acid obtained from plants is alpha linolenic acid. Food sources include flaxseed oil, chia seeds, sage, some vegetables, and nut oils.
Eating a diet rich in omega-3 (from both fish and plant sources) has been associated with a reduced incidence of breast cancer in multiple studies, especially in Asian women [218, 219, 220, 221].
Dietary omega-3 fatty acids reduced the incidence of breast tumors and increased BRCA1 expression in rats. In line with this, treatment with omega-3 fatty acids increased the expression of BRCA1 and BRCA2 in breast cancer cells [222, 223].
In the case of prostate cancer, a clear association hasn’t been observed. Depending on the study, high dietary intake or blood levels of different omega-3 fatty acids increased, decreased, or had no effect on the risk of this cancer type [224, 225, 226, 227, 228].
The effects of omega-3 fatty acids on ovarian cancer have been less widely-investigated and the results were equally mixed: they prevented this cancer type in a study on Swiss and Italian women, but not in an Australian study [229, 229].
12) Discussing Hormone Therapies with a Doctor
Because both estrogen and progesterone can stimulate the growth of tumors that express receptors of these hormones, the role of different hormone therapies in breast and ovarian cancer has been widely investigated.
Postmenopausal women often experience symptoms such as hot flashes and vaginal discomfort because their ovaries stop producing estrogen. Hormone replacement therapy (HRT) with estrogen, usually combined with progesterone to help prevent endometrial cancer, is often prescribed to manage these symptoms.
HRT has been associated with a slightly higher risk of both cancers, especially if combining estrogen and progesterone. However, the results are inconsistent and most doctors agree that the benefits often outweigh the risks [230, 231, 232, 233, 234, 235].
The minor ‘T’ variant of BRCA1 rs799917 polymorphism was associated with an increased incidence of breast cancer in postmenopausal women on estrogen therapy without progesterone. However, other studies found that different mutations at this gene were not associated with breast cancer caused by HRT. This may be due to BRCA1 mutations mainly causing hormone receptor-negative tumors [236, 237, 238].
Similarly, research suggests that carriers of BRCA mutations don’t have an increased risk of developing ovarian cancer from HRT [239, 240, 241].
Hormone-based birth control methods such as oral contraceptives, birth control shots, and implants (IUDs, rings, patches) have also been associated with an increased risk of breast cancer. Conversely, they may help prevent ovarian cancer, possibly because they suppress ovulation [242, 243, 244].
Several studies found that carriers of BRCA mutations, especially BRCA1, are more susceptible to the breast cancer-causing effects of these birth control methods. The risk was especially increased for early-onset breast cancer. If you have a risk variant, you may want to discuss your birth control method with your doctor and maybe shift to one that doesn’t involve taking hormones (such as condoms) [245, 246, 247, 248].
The benefits of hormone-based birth control methods on ovarian cancer prevention have also been observed in carriers of BRCA mutations. Maximum benefit was seen after 5 years of use for BRCA1 mutations and after 3 for BRCA2 mutations. Due to the increased risk of breast cancer from these methods, women with BRCA mutations should consult their use with their doctors [248, 246, 249].
Tamoxifen is a drug that binds to estrogen receptors and blocks their effects in the breasts. For this reason, tamoxifen is used for both the treatment and prevention of estrogen receptor-positive breast tumors.
Multiple studies have associated the use of tamoxifen and similar drugs with a reduced incidence of breast cancer. However, none of them specifically evaluated if BRCA mutations alter its effectiveness [250, 251, 252].
