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Estrogen is the female sex hormone responsible for the growth, development, and regulation of the female reproductive system and secondary sex organs.
The cells that respond to this hormone contain proteins that bind to it and bring about the required effect. These proteins are known as estrogen receptors and are found in female reproductive tissues and cancer cells.
Breast cancers that grow in response to estrogen due to the presence of estrogen receptors are known as estrogen receptor-positive or ER-positive breast cancer.
These cancers grow slower than ER-negative cancers and account for 80% of all breast cancers.
They also have better treatment outcomes in the short term but tend to relapse after years of treatment.
In ER-positive cancers, the growth of cancer cells is estrogen-dependent.
So, hormone therapy drugs can be used to lower estrogen levels in the body or prevent estrogen from affecting breast cancer cells.
Knowing the hormone receptor status of breast cancers can help doctors figure out the ideal treatment plan for the patient.
Women who are carriers of the BRCA1 gene mutations are more likely to develop ER-positive breast cancer as they age.
10-36% of breast cancer cases in people with BRCA1 gene mutations are ER-positive breast cancers.
According to a study, most women with BRCA2 mutations develop ER-positive breast cancer and the treatment outcome for these women may be poorer than BRCA2 carriers having ER-negative breast cancer.
Estrogen exposure plays a significant role in breast cancer. The CYP19A1 or Cytochrome P-450, family 19, subfamily A, contains instructions for the production of aromatase, an enzyme that regulates the final step in the production of estrogen in the body.
Abnormal changes in the CYP19A1 gene are significantly associated with different levels of circulating estrogens
Treatment with Aromatase inhibitor drugs that suppress estrogen production yield better outcomes in ER-positive breast cancer patients with mutations in their CYP19A1 gene.
The ESR1 gene contains instructions for the production of estrogen receptor alpha (a type of estrogen receptor).
Certain changes in the ESR1 gene increase the resistance of cancer cells to hormonal therapy, the standard treatment plan for ER-positive cancers.
- Age: Older women tend to have a higher amount of estrogen receptors, increasing their risk for ER-positive breast cancer.
- Lifetime exposure to estrogen: Women who begin menstruating early, attain menopause late, or do not have children are at a higher risk of ER-positive breast cancer due to longer lifetime exposure to estrogen.
- Alcohol consumption: Alcohol can increase the levels of estrogen and other hormones associated with ER-positive breast cancer. It increases the likelihood of developing ER-positive breast cancer.
- Hormone treatment post-menopause: Women who take hormone therapy after menopause are more likely to develop ER-positive breast cancer.
- Higher BMI (Body Mass Index): Obesity amplifies the risk for ER-positive breast cancer because adipose tissue acts as the major reservoir for estrogen production after menopause.
- History of Breast Lesions: Women with a history of benign growing breast lesions have an increased risk of ER-positive breast cancer.
Some foods like soya, red meat, and dairy have chemicals that function like estrogens.
For this reason, individuals with a high risk of ER-positive breast cancer must avoid them.
They can instead include cancer-fighting foods such as fresh fruits and vegetables (apples, blueberries, asparagus, carrots, tomatoes, etc.), foods rich in fiber (whole grains, oats, etc.), and healthy fats like omega-3 and omega-6 fatty acids.
If you are at high risk of developing ER-positive breast cancer, you must reduce your body fat and limit or completely avoid saturated fats, alcohol, and red meat.
Physical activity and regular exercise reduce ER-positive breast cancer risk.
Aromatase-inhibitor drugs are effective in preventing ER-positive breast cancer.
Note: Aromatase inhibitors should be consumed only upon your medical practitioner's advice.
A BRCA genetic test can help find out your risk for ER-positive breast cancer. Routine breast cancer screening is recommended for those found to be at high risk based on their genetic profile.
Receptors are proteins inside the target cell or on its surface that receive a chemical signal.
Estrogen is an important hormone responsible for various female characteristics in the body, including the growth and development of breasts (or mammary glands).
Estrogen Receptors (ERs) are a type of steroid receptors that attach to estrogen in the blood and regulate the growth and multiplication of cells in the breast. These receptors pick up signals from the hormones and encourage cell growth.
In the case of breast cancer, this growth is uncontrollable and eventually becomes cancerous.
Based on the presence or absence of estrogen receptors in breast cancer cells, there are two types of breast cancers:
A cancer is called estrogen-receptor-positive (or ER-positive) if it has receptors for estrogen. The cancer cells receive signals from estrogen and grow in response to it.
ER-positive is the most common form of breast cancer - around 80% of breast cancers are ER-positive.
Anti-estrogen medications can prevent the growth of these cancer cells.
Breast cancer cells that do not have estrogen receptors are known as estrogen-receptor-negative (or ER-negative) cancers.
ER-negative breast cancer is less common and more challenging to treat. It also often has poor treatment outcomes.
Knowing whether breast cancer is ER-positive or ER-negative helps doctors plan the appropriate treatment.
Every patient with a breast cancer diagnosis undergoes a hormone receptor evaluation that helps determine if the cancer cells have receptors for estrogen and progesterone.
About 2 out of every 3 breast cancer cases test positive for hormone receptors.
Testing breast cancer cells for hormone receptors is important to decide whether hormonal therapy will be an effective course of treatment.
Hormone therapy involves reducing the estrogen levels in the body or blocking the cells from responding to estrogen.
Only if the cancer is ER-positive, hormone therapy will work.
This makes ER-negative cancers difficult to treat; non-hormonal treatments are used for these cancers.
The BRCA2 gene provides instructions for producing a protein that acts as a tumor suppressor (proteins that prevent cells from dividing uncontrollably and rapidly).
The BRCA2 gene is also involved in repairing damaged DNA.
Changes in the BRCA2 gene can increase the risk of different types of cancers, including breast cancer.
Most women with BRCA2 mutations tend to develop ER-positive breast cancer. However, the prognosis may be worse for these women than for those with ER-negative breast cancer carrying BRCA2 mutations.
The MDM4 gene is located on chromosome 1 and produces the MDM4 protein, which regulates a tumor suppressor protein called the p53.
Changes in this gene can affect the protein produced, which in turn interferes with the tumor suppressor activity of p53.
When this happens, it can lead to uncontrolled cell growth resulting in cancer cell formation.
The ZNF365 gene contains instructions to produce the Zinc Finger Protein 365. This protein plays a role in repairing DNA damage. Changes in this gene increase the risk of breast cancer.
A change in the ZNF365 gene, called 19p13.1, has been linked to ER-negative breast cancer in individuals with changes in their BRCA1 and BRCA2 genes.
Race: There is a higher incidence of ER-negative breast cancers in women of African ancestry.
Obesity: Pre-menopausal and menopausal women who are overweight or obese are at an increased risk of developing ER-negative breast cancer.
Alcohol consumption: Increased alcohol intake increases the risk of ER-negative breast cancer.
Younger Age: Hormone receptor-negative cancer is more commonly seen in women around 40 years of age who haven’t attained menopause
Physically active women who have a healthy weight and lead a healthy lifestyle have a reduced risk of developing ER-negative breast cancer.
Even low levels of alcohol intake can increase the risk of breast cancer. The ideal upper limit for alcohol consumption to lower breast cancer risk is one drink a day (12-14 grams of alcohol).
Plant-based diets are packed with fiber, vitamins, and minerals. Fiber helps eliminate excess estrogen (a risk factor for breast cancer). Vitamin C, A, and selenium also play a role in lowering cancer risk.
A 2013 study that followed approximately 30,000 post-menopausal women with no history of breast cancer for 7 years showed that following these three recommendations resulted in a 62% decreased risk of breast cancer.
The BRCA genetic test is a blood test that analyses DNA to detect the presence of harmful changes (mutations) in the BRCA1 and BRCA2 genes. Individuals with these mutations are at a high risk of developing breast cancer. Routine testing for these genes in individuals at high risk is recommended.
Breast cancer is one of the most common types of cancer affecting women. According to the World Health Organization (WHO), 2.3 million women were diagnosed with breast cancer, and 685,000 lost their lives globally in 2020.
As of 2020, 7.8 million women have been diagnosed with breast cancer and are alive in the last five years.
Breast cancer survivors are at risk for different health conditions - fatigue, mental health issues, and breast cancer recurrence - to name a few. They must also be aware of the higher risk they carry for developing a second non-breast cancer.
People who have had breast cancer in the past are at higher risk for developing other types of cancers, including:
A 2006 study collected data from 13 different cancer registries in places like Singapore, Canada, Australia, and Europe. The study analyzed the data of 525,527 women and followed them for 10+ years.
According to the study, when compared to women who did not have a history of breast cancer, women with past or present breast cancer had:
Another study analyzed the risk of Secondary Non Breast Cancers (SNBCs) in 58,068 Dutch women diagnosed with breast cancer between 1989 and 2003. According to the study, women who had breast cancer in the past had a small but significant risk for developing esophageal cancer, stomach cancer, colon cancer, rectum cancer, uterus cancer, ovarian cancer, soft tissue sarcoma, acute myeloid leukemia (AML), and non-Hodgkin’s lymphoma.
The BRCA1 gene (BRCA1, DNA repair associated gene) produces a tumor suppressor protein. This protein is considered beneficial as it hinders uncontrolled cell division, thereby lowering cancer risk.
Abnormal changes (or variations) in this gene can lead to low or no production of the tumor suppressor protein and increase one’s risk for developing cancers.
A study reported that BRCA1 variations lead to breast and ovarian cancers and also increase the risk of other cancers like colon cancer (11.1%), pancreatic cancer (3.6%), and gastric cancer (5.5%).
The BRIP1 gene (BRCA1 interacting protein C-terminal helicase 1) contains instructions for producing a protein that repairs double-strand breaks in DNA.
Abnormal changes in this gene result in lower production of this protein, which increases the risk of many types of cancers. Cancers associated with variations in this gene are:
The PALB2 gene (Partner And Localizer Of BRCA2 gene) contains instructions for producing a protein that works with the BRCA2 protein to repair damaged DNA and suppress tumor growth. Abnormal changes in this gene affect the ability of the BRCA2 gene to prevent tumor cell formation.
Apart from breast cancer, this gene is associated with the risk for:
The CHEK2 gene (Checkpoint kinase 2) is also a tumor suppressor gene and produces a kinase enzyme protein called CHK2.
Abnormal changes in this gene increase the risk of developing breast cancer by two times. It also increases the risk of:
The PTEN gene produces an enzyme that acts as a tumor suppressor. Almost all tissues in the body have this enzyme in specific quantities. This enzyme prevents the abnormal division of cells by encouraging self-destruction (a process called apoptosis) of these cells. In people with past or present breast cancer diagnoses, variations in this gene can result in an increased risk of:
One of the main non-genetic factors that increase a person’s risk of developing other cancers is radiation exposure.
There are three basic radiotherapy treatment solutions for breast cancer.
1. Three-dimensional Conformal Radiotherapy (3D-CRT)
2. Intensity-Modulated Radiotherapy (IMRT)
3. Volumetric Modulated Arc Therapy (VMAT)
Many studies report a higher risk of second cancer because of radiation exposure.
A large study analyzed the risk of second cancers in 46,176 breast cancer survivors. According to the study, one out of 200 women who had received radiation therapy for breast cancer had a higher risk of being diagnosed with other cancers.
Chemotherapy is a treatment that uses various drugs to kill abnormally growing tumor cells in the body. It is the most common treatment option for cancer.
Some types of chemo drugs given during breast cancer treatment are associated with an increased risk for developing other types of cancers.
Chemo agents that are linked with second cancer risks are:
Patients who go through chemotherapy for a longer time or get treated with higher doses of drugs are at a higher risk of developing other cancers.
While patients who had exposure to radiation therapy and chemotherapy were at higher risk for developing second non-breast cancers, people under the age of 40 who received these treatments were at more risk than the elderly who received treatment.
Smoking increases the risk of breast cancer and all other cancers. Smokers diagnosed with breast cancer are at higher risk for developing other cancers in the future when compared to non-smokers.
A 1994 study tried to find the relationship between smoking, breast cancer, radiation therapy, and the risk of second cancers. According to the study, radiation therapy for breast cancer increased the risk of developing other cancers in smokers and non-smokers. However, in smokers, this risk was much higher.
Genetic testing can be a good aid for treatment planning and risk management if:
Genetic testing will look for specific genes that can increase your risk for breast and other cancers. It will tell you if you are at higher risk for second cancer. In case you belong to the high-risk category, regular screening can help you.
Talk to your doctor about the dosage and type of chemotherapy and radiation treatment you will be receiving for your breast cancer. Some treatments may increase your risk for breast cancer than others.
Some lifestyle changes can lower your risk of developing cancer.
The fear of breast cancer recurrence and the fear of developing second cancers can lead to high stress. Stress causes abnormal changes in the cells and can be a cause for cancer recurrence. Fear and stress lead to unwanted behaviors like alcohol abuse, smoking, and excessive eating. All these also increase the risk of developing other cancers. Practicing mindfulness and talking to a mental health expert might help you in controlling stress.
Smoking remains one of the biggest causes of preventable deaths globally. According to the Centers for Disease Control and Prevention (CDC), smoking accounts for 1 in about five deaths in the United States every year.
As of 2019, 14% of the adult population in the country are smokers.
The American Lung Association states that there are more than 600 ingredients present in a cigarette. Each cigarette releases about 7000 chemicals when it is burnt. Out of these, close to 70 chemicals are proven carcinogens (cancer-causing substances). Some of them are:
When a person inhales cigarette smoke, these carcinogens and other chemicals reach the lungs and are distributed throughout the body.
Once these carcinogenic chemicals enter the body, they are detoxified by the cytochrome P450 group of enzymes (CYPs).
These CYP enzymes convert these carcinogens into a more active intermediary form called DNA adducts. DNA adducts are parts of the DNA that attach themself to these cancer-causing chemicals.
The intermediaries lead to DNA damage and abnormal cell multiplication and have to be quickly detoxified by other enzymatic processes. Unfortunately, in some people, the number of cancerous intermediaries builds up at a faster rate than they are eliminated. This leads to cancer.
There are other carcinogens in cigarette smoke that directly form DNA adducts without the help of the CYP enzymes. These lead to direct DNA damage and cell abnormalities, and resultant cancer.
While smoking is a risk factor for all types of cancer, it is significantly associated with breast cancer in women.
In the United States, 1 in every eight women will be diagnosed with breast cancer in her lifetime. Smoking increases this risk drastically.
A study published in the BioMed Central Ltd forum analyzed the risk of breast cancer in women who smoked.
102,927 women were chosen and monitored for 7.7 years. In the end, 1815 women developed invasive breast cancer. The study found that smokers had a 14% higher risk of developing breast cancer than non-smokers.
Learn More: How Genes Influence Your Risk for Nicotine Dependence?
This study also mentions that women who start smoking before 17 had a significantly higher risk (24%) for breast cancer.
Another study analyzed the risk of breast cancer in 111,140 active smokers and 36,017 passive smokers (people who don’t smoke themselves but are exposed to other people’s cigarette smoke).
According to the study, some factors that increase the risk of breast cancer are:
Secondhand smoke is also called passive smoking and is smoke that a person inhales unintentionally. For example, people can inhale tobacco smoke by just being around others who smoke. According to the California Air Resources Board, secondhand smoke is a proven carcinogen.
The smoke that is released from the burning ends of cigarettes is called sidestream smoke. Sidestream smoke is unfiltered and hence contains more harmful substances than the smoke that a smoker breathes out.
A 2013 study analyzed the risk of breast cancer in 322,988 active, passive, and non-smokers.
Compared to non-smoking women, those exposed to passive smoke at home or work had a higher risk of developing breast cancer.
The GSTM1 gene (glutathione S-transferase mu 1 gene) helps produce the glutathione S-transferase enzyme that belongs to the Mu class. The Mu class of enzymes helps in eliminating carcinogens and other environmental toxins from the body.
rs366631 is a single nucleotide polymorphism or SNP in the GSTM1 gene.
People with the GSTM1 null genotype have a higher risk of developing breast cancer when exposed to cigarette smoke.
Null genotype is the non-functional variant of the gene that results in total loss of function of the gene.
Here, the TT genotype is the null genotype.
The risk of breast cancer was also more severe in postmenopausal smokers with the GSTM1 null genotype.
| Genotype | Implication |
| TT | Increased risk of breast cancer upon smoking |
| CT | Normal risk of breast cancer upon smoking |
| CC | Normal risk of breast cancer upon smoking |
The SLC4A7 gene (Solute Carrier Family 4 Member 7 gene) helps produce a protein that transports sodium and bicarbonate ions. It also plays a role in the metabolism of different acids, ions, and amine compounds.
rs4973768 is an SNP in the SLC4A7 gene. A meta-analysis has reported an increased risk for breast cancer upon smoking in T allele carriers.
| Genotype | Implication |
| TT | Increased risk of breast cancer upon smoking |
| CT | Increased risk of breast cancer upon smoking |
| CC | Normal risk of breast cancer upon smoking |
There are so many government and private bodies that help people with tobacco addiction. You can get help from some of these rehab centers to stop or limit smoking. It takes time and effort to curb the craving. Here are some pointers that can help you with this.
For people who have been smoking for years together, some places, smells, habits, or environments can create an urge to smoke. Understand these triggers and stay away from them. Practice the below activities to make quitting smoking easier.
Secondhand smoking ends up harmful to non-smokers. Here are ways you can limit/eliminate secondhand smoke exposure.
Genetic testing helps identify genetic factors that could increase your breast cancer risk. If you do have a high genetic risk, regular screening may help.
Radiation is the transmission of energy through space or a medium. The transmission is in the form of waves or particles. Some radiation is naturally created, while others are artificially made.
There are two types of radiation depending on how they affect other atoms and molecules.
Non-ionizing radiation: This is the type of radiation that human beings are regularly exposed to. The radiation is not strong enough to affect atoms and molecules in the body.
Types of non-ionizing radiation
Ionizing radiation - This radiation is strong enough to ionize atoms and molecules. Ionization is the process of removing an electron from an atom and making it positively charged. Ionization causes electron/proton imbalance in the atoms, and this affects the cells in the body.
| Types of ionizing radiation | |
| Alpha radiation | It consists of two protons and two neutrons. It cannot penetrate past the outer skin and causes no damage |
| Beta Radiation | It consists of fast-moving electrons. It can penetrate the outer skin and is used to treat superficial tumors. |
| Gamma Radiation | It consists of protons that have neither electric charge nor mass. As a result, the radiation penetrates through the skin and leads to cell damage. |
| X-rays | X-rays are man-made electromagnetic radiation. X-rays are similar to gamma rays and can penetrate the human body. |
| Neutron radiation | It consists of free neutrons produced in large numbers due to nuclear fission or fusion reactions. |
There are two categories of ionizing radiation sources - natural and artificial.
Natural Sources Of Ionizing Radiation
According to the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), there are four natural sources of ionizing radiation.
Artificial Sources Of Ionizing Radiation
Radiation exposure can cause breast cancer in different ways.
Researchers studied the effect of radiation exposure on Japanese women who survived the atomic bombing of 1945. The study identified 807 first-time breast cancer cases and 20 second-time breast cancer cases in the survivors. The study reported the following:
Mammography is a diagnostic procedure that uses X-rays to check for breast cancers. In a diagnostic mammogram, a minimum of two X-ray films of the breasts is taken at two different angles. On average, the dose of radiation for these two pictures is 0.42 mSv (millisieverts). Dosage is the amount of ionization that occurs due to radiation exposure.
According to the National Breast Cancer Foundation, women over 40 years are advised to get their annual mammographic screening done. In addition, doctors may recommend more frequent screening in the following cases.
According to a study, women with large, dense breasts who undergo repeated mammography may be at higher risk for radiation-induced breast cancer and breast cancer death.
The researchers projected that "annual digital mammographic screening of 100,000 women (aged 40 to 74) would induce 125 cases (~0.1%) of breast cancer, and that there would be 16 deaths (0.016%)."
However, this number appears to be almost negligent when compared to the 968 breast cancer deaths (9.7%) that would have been averted by early detection from screening.
The H19 gene helps produce a molecule called the non-coding RNA. The non-coding RNA is considered to be a tumor suppressor and is protective against different kinds of cancers. Certain changes in this gene can encourage the growth and multiplication of radiation-damaged cells. This can lead to tumors.
rs2107425 is a single nucleotide polymorphism or SNP in the H19 gene. A particular study reports that people with the A allele of this SNP, are at a higher risk for developing breast cancer when exposed to high doses of radiation.
The ERCC2 gene helps make a protein called XPD (Xeroderma Pigmentosum complementation group D). It plays a role in repairing damaged DNA.
rs13181 is an SNP in the ERCC2 gene. In people with the wild AA genotype of this SNP, there is an association between occupational radiation exposure and breast cancer.
However, this association is not seen in the AC and CC genotypes.
| Genotype | Implications |
| AA | Association between occupational radiation exposure and breast cancer |
| AC | No association between occupational radiation exposure and breast cancer |
| CC | No association between occupational radiation exposure and breast cancer |
Studies show that women under 20 are at the highest risk for developing breast cancer due to radiation exposure. According to these studies, women above 50 years have minimal or no recorded risk for radiation-induced breast cancer.
Few women may have undergone radiation therapy in the past, increasing the risk of breast cancer. Some women who are in the high-risk category include:
The periods of pregnancy bring down the risk of radiation-induced breast cancer. Women who have an early full-term pregnancy are more protected against breast cancer.
According to some studies, during pregnancy and breastfeeding, the number of weak breast cells affected by radiation is lesser, bringing down breast cancer risk.
Family history affects the relationship between radiation exposure and breast cancer. The Family history affects the relationship between radiation exposure and breast cancer. The BRCA1 and BRCA2 gene changes lead to inherited breast cancer.
Women with changes in these genes are already at a higher risk of developing breast cancer. Radiation exposure can increase the risk.
According to the American Cancer Society, women between the ages of 40 and 44 can start screening for breast cancer but don’t have to get mammograms unless their doctors instruct. Women between 45 and 54 need to get one mammogram a year. Women older than 55 should get two mammograms done a year.
If you are younger than 40, talk to your doctor and only get a mammogram if necessary. While mammogram screening helps identify tumors early and treat breast cancer early, getting unnecessary mammograms may trigger breast cancer in a few.
Occupational radiation exposure happens in workplaces when the person handles radioactive sources or works with equipment generating radiation.
Lifestyle habits like smoking and drinking, excessive weight gain, the types of food you choose, and exposure to other environmental carcinogens can all lead to breast cancer.
Unhealthy lifestyle choices, along with radiation exposure, increases breast cancer risk drastically.
Genetic testing will help identify how harmful radiation exposure is for your breast cells. You can also know if you are at risk for developing inherited breast cancer because of the abnormal functioning of the BRCA1 and BRCA2 genes.
Did you know that our ancestors were nocturnal? They used to stay awake in the night to hunt without worrying about dangerous predators and sleep during the day. Now, our circadian rhythms are lined up with the sun. That's why as soon as the sun sets, our bodies start getting ready for rest, and we end up feeling sleepy.
Circadian rhythms are biological cycles that coordinate essential mental and physical functions, such as sleep and hunger. The circadian clock is regulated by a part of the brain called the Suprachiasmatic Nucleus (SCN).
The circadian clock is also influenced by temperature. When the body temperature drops around the afternoon and late evening, it induces drowsiness and sleep.
Sleep is induced by a hormone called melatonin, which is produced in low-light conditions. Bright light conditions during the day suppress melatonin production and promote wakefulness.
People who work the night shift have disrupted circadian rhythm and have an increased risk for the following conditions:
Working the night shift is carcinogenic to humans, according to multiple studies conducted the world over.
Several studies show that disruption in the night’s sleep can reduce melatonin levels and increase the risk of tumor growth.
Some animal studies have shown that exposure to light at night led to the growth of breast cancer.
The risk of breast cancer among nurses and other night-shift workers seems to be higher than their counterparts who worked day shifts.
A study published in the Journal of National Cancer Institute in 2001 reported that women who work in rotating night shifts for at least three nights per month, along with day shifts, have a moderately high risk of breast cancer.
Further, the risk seems to be higher when the night shifts per week increase!
This increased risk is attributed to the messed-up melatonin levels in the body.
In addition to promoting sleep, melatonin also stops tumor growth and protects against the spread of cancer cells.
When melatonin levels decrease in the body, it results in an imbalance of inflammatory cytokines, increased mutations in the cells, and oxidative damage (due to free radicals).
These events can all trigger cancer development.
A reduction in melatonin also affects estrogen levels, which further increases the risk of breast cancer.
A long duration of shift work throughout the years is associated with estrogen and progesterone-positive tumors.
When the circadian rhythm is altered, it changes the expression of the CLOCK genes. This also influences the production of reproductive hormones.
The Neuronal PAS Domain Protein 2 or NPAS2 gene is the largest circadian gene. It plays a vital role in sleep homeostasis and circadian rhythm regulation.
This gene also regulates the cell cycle and works with certain other genes for repairing DNA. The NPAS2 gene shows a strong association with breast cancer.
rs2305160 (Ala394Thr) is an SNP (Single Nucleotide Polymorphism) in the NPAS2 gene.
Among women with little or no exposure to shift work, the A allele (AA or AG) is associated with a significantly lower risk of breast cancer.
However, among women with AA genotype who had worked >2 years of rotating night shifts, the risk of breast cancer was nearly 3 fold compared to women with the same genotype with <2 years of night shift work.
| Genotype | Implication - > 2 years of rotating night shifts |
| AA (Thr/Thr) | ~3 fold increased risk of breast cancer |
| AG (Thr/Ala) | Slightly increased risk of breast cancer |
| GG (Ala/Ala) | Normal risk of breast cancer |
Use Xcode Life’s Free Gene Tool To Find Out If You Have The Risk Genotype!
RAR-Related Orphan Receptor A or the RORA gene is located on chromosome 15 and regulates genes involved in the body’s circadian rhythm.
rs1482057 is an SNP in the RORA gene. A study published in 2014 showed that SNP rs1482057 was associated with breast cancer in postmenopausal women.
Women who have at least one A allele and had a history of working night shifts in their lifetime had a higher risk of developing breast cancer.
Conversely, women having the CC genotype and working night shifts showed a decreased risk of breast cancer.
| Genotype | Implication |
| AA | Increased breast cancer risk on night shift work |
| AC | Increased breast cancer risk on night shift work |
| CC | Decreased breast cancer risk on night shift work |
Cryptochrome circadian regulator 2 or the CRY2 gene gives instructions to produce a protein involved in regulating the body’s circadian rhythm.
rs2292912 is an SNP in the CRY2 gene, located on chromosome 11. Night shift working increased the risk of breast cancer in women who carried the CG genotype of rs2292912 SNP.
| Genotype | Implication |
| CG | Increased breast cancer risk on night shift work |
| GG | Decreased breast cancer risk on night shift work |
| CC | Decreased breast cancer risk on night shift work |
Since working night shift hours increases the risk of breast cancer in women, one of the most effective ways to lessen this risk is to reduce working night shifts.
Switching with a colleague’s shift, alternating your night shifts with day shifts, or switching jobs can be a few ways by which you can reduce your night shift hours.
Apart from disrupting the sleep-wake cycle, disturbed sleep or poor quality of sleep in people who work night shifts can increase their risk for breast cancer.
So, if you are working a night shift, ensure you get your 7-8 hours of sleep every day. If you have trouble sleeping, consult your doctor about supplements that can help you catch up on your daily sleep.
People working the night shift must try and reduce other risk factors of breast cancer.
A healthy diet with lots of fruits, limited alcohol consumption and smoking, adequate physical activity, and reduced exposure to harmful chemicals can help reduce breast cancer risk.
Regular exercising comes with a range of health benefits, one of which is reduced risk for developing breast cancer. Many studies conducted over the last 20 years have consistently reported a lower risk of breast cancer among women engaging in regular physical activity.
However, the exact mechanism behind this is unclear. Being active may lower estrogen levels in the body. Studies have shown that women with lower blood estrogen levels have a lower risk of breast cancer than women with higher levels.
Adipose tissue is the primary source of estrogen in postmenopausal women. So, reducing body fat with exercise can lower estrogen production and significantly reduce breast cancer risk in postmenopausal women.
In addition, exercise also reduces inflammation in the body, strengthens the immune system, decreases insulin resistance, and reduces oxidative stress – all of which are risk factors for breast cancer development.
A study published in The Journal of the American Medical Association in 2005 reported that physical activity after breast cancer diagnosis might reduce the risk of death due to the disease.
Women who performed physical activity equivalent to walking for 3 to 5 hours per week at an average pace benefited the most.
The study also reported that physical activity after breast cancer diagnosis reduced the chances of recurrence and improved the quality of life in these women.
The primary reason cited for the reduced risk is the low levels of circulating estrogen.
A study conducted in 2015 reported that weight loss by exercise resulted in an increase in lean mass, greater fitness, and a positive effect on the serum sex hormone levels due to greater loss of body fat.
These effects have been associated with a decreased risk of postmenopausal breast cancer.
A systematic review analysis was conducted and published in 2019, wherein researchers studied 38 cohort studies published between 1994 and 2017 comprising 68,416 breast cancer cases.
The researchers observed that the risk for breast cancer was significantly lower in people with exposure to physical activity longer than a year but less than five years, followed by those who had a lifetime exposure to physical activity.
In a study published in 2014, the authors found that breast cancer and colorectal cancer survivors, who increased their physical activity before or after their cancer diagnosis, showed a decreased mortality risk compared with those who were inactive or did not change their physical activity levels.
5-methyltetrahydrofolate-homocysteine methyltransferase reductase or MTRR gene gives instructions for producing the enzyme methionine synthase reductase, which is required for the normal functioning of enzyme methionine synthase.
Certain changes in the MTRR gene can induce insulin resistance, thereby making the cells unresponsive to insulin. This can result in type 2 diabetes.
Previous studies reported the association of this genetic change with lung and colorectal cancers, but not with breast cancer.
A 2019 study examined the effect of genetically driven insulin resistance on breast cancer risk.
The researchers identified a Single Nucleotide Polymorphism (SNP) rs13188458 in the MTRR gene. It was found that, in a group of physically inactive people, those with the T allele of this SNP had a greater risk for abnormally high insulin levels (hyperinsulinemia) and breast cancer than people with the G allele.
| Allele | Implication |
| T | Higher risk for hyperinsulinemia and breast cancer when physically inactive |
| G | Normal risk for hyperinsulinemia and breast cancer when physically inactive |
ERCC Excision Repair 4, Endonuclease Catalytic Subunit or ERCC4 plays an essential role in repairing damaged DNA. A defect in this gene has been associated with Xeroderma pigmentosa, a skin condition.
A meta-analysis done in 2011 revealed an association between ERCC4 and breast cancer risk. rs1800067 is an SNP in the ERCC4 gene.
Postmenopausal women with the GG genotype of this SNP who engaged in >9.23 hours of recreational physical activity per week experienced statistically significant reductions in breast cancer risk.
| Genotype | Implication |
| GG | Significant reduction in breast cancer risk with exercise |
| AG | Modest reduction in breast cancer risk with exercise |
| AA | Normal risk of breast cancer with exercise |
The MLH1 or MutL homolog 1 gene is a part of MMR or mismatch repair set of genes. It repairs damaged DNA by replacing the portion containing the errors with the corrected sequence.
rs1799977 is an SNP in the MLH1 gene. Women with the G allele of this SNP who were active during the postmenopausal years experienced significant breast cancer risk reductions.
| Allele | Implication |
| G | Significant reduction in breast cancer risk with physical activity in postmenopausal women |
| A | Normal breast cancer risk with physical activity in postmenopausal women |
Researchers have observed that postmenopausal women who exercise for at least 300 minutes per week can successfully reduce their body fat compared to those who spent half that time.
Even 2.5 hours of brisk walking per week can reduce breast cancer by as much as 18%!
If you are in a dilemma about how to begin your exercise, here are some handy and effective tips to help you exercise the right way to keep breast cancer at bay:
Excess body weight is responsible for about 11% of cancers in women and 5% of men. Did you know that the risk for postmenopausal breast cancer is 1.5 times higher in overweight women and 2 times higher in women with obesity? Let’s understand more about how obesity contributes to breast cancer risk.
Being overweight or obese increases the risk for breast cancer, especially in postmenopausal women. Your Body Mass Index (BMI) determines if you have a healthy weight, are overweight, or are obese.
A BMI between 18 and 24.9 is considered healthy. A BMI between 25 and 29.9 means that you are overweight. If your BMI is higher than 30, it could indicate obesity.
Women with a BMI over 25 are at an increased risk of developing breast cancer than those with a healthy weight. In addition, this risk is exceptionally high after menopause. Being overweight or obese also increases the risk of breast cancer recurrence.
The exact link between increased weight and breast cancer risk is complicated and multifactorial. The high risk appears to be connected to the estrogen production by the fat cells.
In premenopausal women, estrogen is mainly produced by the ovaries. However, in postmenopausal women, adipose tissues or fat tissues is the main source of estrogen production.
The number of fat cells is higher in overweight or obese women. This results in increased estrogen production, which is a risk factor for breast cancer development. This is especially of significance for Hormone-Receptive breast cancers that develop and grow on exposure to estrogen.
It has been found that women who are obese after menopause are at a 30% higher risk of developing breast cancer. Gaining more than 22 pounds after menopause can increase the risk of breast cancer by 18%.
Studies report an association between obesity and a lower risk of Estrogen-Receptor Positive (ER-Positive) breast cancer but a higher risk of ER-negative and Triple-negative breast cancer in premenopausal obese women.
In addition, a study from the Breast Cancer Surveillance Consortium database showed that obesity is associated with an increased risk for Inflammatory Breast Cancer (IBC) in premenopausal women.
The Million Women Study followed 1.2 million UK women ages 50 to 64 years for a mean of 5.4 years. Out of these, 45,037 women had breast cancer. The study identified a nearly 30% higher risk of developing postmenopausal breast cancer with obesity.
A meta-analysis of 34 studies reported that the risk of postmenopausal breast cancer increases with every 5kg/m2 increase in BMI.
Obesity affects the prognosis and survival rate of breast cancer patients. A recent study found that obese women with breast cancer experienced an 11% decrease in overall survival rate, irrespective of their menopausal status.
Besides breast cancer, obesity is a risk factor for type 2 diabetes and heart diseases - the latter seems to be the leading cause of mortality in women with early-stage breast cancer.
It has also been observed that obese women with breast cancer are more likely to experience complications during surgery and radiation.
In addition, systemic chemotherapy and endocrine therapy for treating breast cancer are less effective in obese women, further reducing prognosis and survival rate.
Breast cancer-specific mortality among obese women is 1.3 times higher compared to women with a normal BMI.
The mortality rate in obese women is also dependent upon the type and characteristics of the tumor. For example, obese women with Luminal A and Luminal B breast cancer were 1.8 and 2.2 times more likely to die from cancer than normal-weight women.
However, obesity was not associated with breast cancer-specific mortality among women with HER2- and triple-negative tumors.
BRCA1 Interacting Helicase 1 (BRIP1) is located on chromosome 17 and, along with the BRCA1 gene, helps repair any damage to the DNA. It is also responsible for maintaining chromosomal stability.
rs16945628 is a Single Nucleotide Polymorphism (SNP) in the BRIP1 gene. The TT genotype of this SNP is associated with an increased risk of breast cancer in women with a BMI of ≧25 kg/m2.
Insulin-like Growth Factor Binding Protein 3 or IGFBP3 gene is located on chromosome 7 and participates in cell growth, multiplication, and differentiation, and cancer development in the breast tissue.
rs2854744 is an SNP in the IGFBP3 gene linked to the risk of breast cancer. The CC genotype of this gene significantly increases the risk of breast cancer compared to the AA genotype. This increase was found to be more pronounced in older women.
Studies also showed that women carrying the AC+CC genotypes of the IGFBP3 gene had a larger tumor size in the breast.
Obesity is a critical non-genetic risk factor for breast cancer.
Other factors that increase breast cancer risk in obese women are:
According to a 2019 study, sustained weight loss is associated with lower breast cancer risk for women aged 50 years and older.
The researchers looked at 180,885 women from 10 studies. The women's weights were recorded 3 times over a period of 10 years; once when they enrolled and once every 5 years.
Weight changes of 2 kilograms or less (about 4.4 lbs) were counted as stable.
The study reported the following*:
*Compared with those whose weight was stable.
The study did not include women on postmenopausal hormone therapy, and the results were more prominent in obese or overweight women.
Despite this, the study suggests that even a modest amount of sustained weight loss can lower your breast cancer risk and improve survival rate, if diagnosed with breast cancer.
Triple-negative breast cancer (TNBC) is one of the aggressive subtypes of breast cancer that occurs in women. Unfortunately, the prognosis and management of TNBC pose great difficulty. However, a new study by the University of Texas M. D. Anderson Cancer Center reports an association between statin use and improved survival rates among TNBC affected individuals.
TNBC is a subtype of breast cancer that lacks any receptors generally found in breast cancer cells. The other types of breast cancers have receptors for any of these hormones:
*Note: Receptors are proteins that receive chemical signals by binding to specific molecules.
TNBC represents about 10-15 % of all breast cancers.
The presence of even one of the receptors makes treating breast cancer easier. Doctors can then treat cancer by targeting these receptors to get inside the cancerous cell and destroy it.
However, in TNBC, the lack of receptors limits the treatment options.
According to the American Cancer Society, based on diagnosis information between 2010-2016, the 5-year survival rate for TNBC affected individuals is 77%. However, these statistics are subject to variation depending on the cancer progression stage and grade of the tumor.
Know about your BRCA status and risk for breast cancer using Xcode Life’s BRCA and Breast Cancer Report.
Statins represent a class of drugs usually prescribed for heart attacks and stroke. Statins help in lowering blood cholesterol levels.
Statins can be broadly classified into lipophilic and hydrophilic statins. Lipophilic statins are fat-soluble, and hydrophilic are water-soluble.
Notably, lipophilic statins quickly enter the cells and communicate with cell membranes. In contrast, hydrophilic statins show more selectivity to liver cells.
Explore your body’s response to different types of statins with Xcode Life’s Personalized Medicine report.
The earliest research to report a link between statin and TNBC was a study in 2013. According to the study, statins activate the inhibition of TNBC through the PI3K pathway. They also suggested Simvastatin as a potent candidate for the treatment of TNBC, especially for wild-type (a form of the gene occurring naturally and predominating a population) expression of PTEN in the TNBC tumors.
Another study, done in 2017, to investigate the outcome of statin use on TNBC produced mixed results. The study observed no apparent association between statin use and overall survival (OS) in an unselected cohort of TNBC patients.
However, statin use significantly improved OS within a specific group of test subjects whose cholesterol and triglyceride levels were controlled. In addition, statin use showed a pronounced effect on survival rate even for another group of triple-negative patients who experienced metastatic failure.
*Note: 1. Overall survival: Length of time from the diagnosis date or start of treatment that a patient is still alive.
2. Metastasis: Stage of cancer where the cancerous cells start migrating from their origin site and infect other healthy parts of the body.
In 2019, a study found that the effect of statin use on breast cancer survival depended on the duration of statin use. In the test subject group, patients who had a medical history of statin use for more than five years experienced a conspicuous improvement in survival rate.
(NB: The findings of the study were irrespective of breast cancer type or receptor subtype)
In 2020, a statistical study on the clinical outcome of statin use on breast cancer diagnosis involving multiple research studies found a significant association between statin use and decreased recurrence rate and breast-cancer mortality in women.
| Year | Study | Outcome |
| 2013 | Statin induces inhibition of triple negative breast cancer (TNBC) cells via PI3K pathway. | Statin activates inhibition of TNBC through the PI3K pathway |
| 2017 | Impact of Statin Use on Outcomes in Triple Negative Breast Cancer. | Statin use improved survival rates in TNBC patients who:Had their cholesterol and triglyceride levels controlledExperienced metastatic failure |
| 2019 | Impact of long-term lipid-lowering therapy on clinical outcomes in breast cancer. | Long-term (>5 years) use of statin improved survival rates in TNBC patients |
| 2020 | Association Between Statin Use and Prognosis of Breast Cancer: A Meta-Analysis of Cohort Studies. | Significant link between statin use and decrease in the recurrence rate of TNBC and disease-specific mortality in women. |
A study led by Kevin Nead of the University of Texas M. D. Anderson Cancer Center explored the outcomes of statin use in breast cancer patients. This study was the first to investigate the effect of statin use on all subtypes of cancer, focusing mainly on TNBC.
According to Nead, “Previous research has looked at breast cancer as only one disease, but we know there are many subtypes of breast cancer, and we wanted to focus our research on this particularly aggressive form of breast cancer that has limited effective treatment options.”
The study analyzed 23,192 female patient data included in the Surveillance, Epidemiology, and End Results (SEER)-Medicare registry and the Texas Cancer Registry (TCR)-Medicare databases between 2008-2015. Patients were at least 66 years of age and diagnosed with stage I-III breast cancer.
2281 patients out of 23,192 were individuals who commenced statin use within 12 months of a breast cancer diagnosis. Out of these 2281 patients, 78.1% were white, 8.9% were black, 8.4% were Hispanic, and 4.5% belonged to other races.
The study also assessed the type-specific effect of statin on breast cancer outcomes.
