Breast Cancer (Mammary Carcinoma): Causes

Pathogenesis (disease development)

It is not exactly clear which causes are responsible for the development of breast carcinoma. In most cases, the disease occurs spontaneously.Even more than for the familial forms of breast carcinoma, genetic defects are responsible for the spontaneous development of this carcinoma. In 40 percent of patients with breast carcinoma, a p53 mutation is present as an acquired defect.

Furthermore, breast carcinoma is mostly (> 50%) a hormone-dependent disease. The carcinoma develops via in situ stages. Whether carcinoma develops from normal cells or cells that have already undergone primary atypical changes is still unclear.

Etiology (Causes)

Biographic causes

Genetic burden
- Approximately 30% of all patients with breast carcinoma have a familial burden.
- In siblings or daughters of women with breast cancer.
- Genetic risk depending on gene polymorphisms:
  - Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
    - Genes: BRCA1, BRCA2, CASP8, FGFR2, GPX4, PALB2, PLSCR3, XXCC2.
    - SNP: rs796856605 in the BRCA1 gene.
      - Allele constellation: DI (BRCA1 mutation).
      - Allele constellation: DD (BRCA1 mutation)
    - SNP: rs80357906 in the BRCA1 gene.
      - Allele constellation: DI (BRCA1 mutation).
      - Allele constellation: DD (BRCA1 mutation)
    - SNP: rs80359550 in the gene BRCA2
      - Allele constellation: DI (BRCA2 mutation).
      - Allele constellation: DD (BRCA2 mutation)
    - SNP: rs180177102 in the PALB2 gene.
      - Allele constellation: DI (3-5-fold).
    - SNP: rs2981582 in the FGFR2 gene.
      - Allele constellation: CT (1.3-fold for ER+ breast carcinoma, 1.08-fold for ER- breast carcinoma).
      - Allele constellation: TT (1.7-fold for ER+ breast carcinoma, 1.17-fold for ER- breast carcinoma).
    - SNP: rs3803662 in the gene PLSCR3
      - Allele constellation: TT (1.6-fold).
    - SNP: rs889312 in an intergenic region.
      - Allele constellation: AC (1.22-fold).
      - Allele constellation: CC (1.5-fold)
    - SNP: rs713041 in gene GPX4
      - Allele constellation: CT (1.3-fold).
      - Allele constellation: TT (1.3-fold)
    - SNP: rs1045485 in the gene CASP8
      - Allele constellation: CG (0.89-fold).
      - Allele constellation: CC (0.74-fold)
    - SNP: rs3218536 in gene XXCC2
      - Allele constellation: AG (0.79-fold).
      - Allele constellation: AA (0.62-fold)
  - With mutations in the BRCA1 or BRCA2 gene, there is a 2 to 9-fold increased risk of developing disease!In women with a BRCA mutation, the risk – over a lifetime (lifetime risk) – of developing breast cancer is circa 60 to 80%. The risk of developing ovarian cancer is about 40 to 60 percent for BRCA1 mutation carriers and about 10 to 30 percent for BRCA2 mutation carriers. In women with a BRCA1 mutation, a single pregnancy increases the risk of breast cancer; the risk decreases again with further pregnancies. Likewise, long periods of breastfeeding (>24 months) reduce the risk of breast cancer of BRCA1- carriers by 24%..In women with a BRCA2 mutation, a single pregnancy also increases the risk of breast cancer; a protective effect was only apparent after the fourth child.
  - Mutations in the BRCA1 or BRCA2 genes account for only 22-55% of hereditary breast carcinomas. All other mutations known to date are rare and have low penetrance (risk of disease). For this reason, it is not looked for in genetic testing.
  - In BRCA1 carriers, the disease peak is reached ten years earlier than in BRCA2 carriers. Until the age of 80 years develop the disease
    - BRCA1 mutations: 72% (incidence increases by age 30 to 40 years).
    - BRCA2 mutations: 69% (peak at age 40 to 50 years).
    The risk of ovarian cancer is slightly lower than for breast cancer, at 44% for BRCA1 and 17% for BRCA2.
  - BRCA3 mutation (RAD51C) carriers also have a significantly increased risk of breast and ovarian cancer. However, the frequency of RAD51C and RAD51D germline mutation carriers in high-risk families is estimated to be only about 1.5% to a maximum of 4% (BRCA1: about 15%, BRCA2: about 10%).The lifetime risk of breast cancer is reported to be approximately 60% to 80% in RAD51C and RAD51D mutation carriers, and the risk of ovarian cancer is reported to be approximately 20% to 40%.
  - Overexpression of the HER2-neu oncogene on chromosome 17 and adjacent regions on the same chromosome.
  - PALB2 gene: one in three women with a mutation in the PALB2 gene developed breast cancer during her lifetime
  - Mutations in 5 cancer genes (in addition to BRCA1, BRCA2, these were BARD1, PALB2, and RAD51D) increase the lifetime risk of triple negative breast cancer (“TNBC”) by 5-fold; tumor cells do not have receptors for the hormones estrogen or progesterone or HER2 (human epidermal growth factor receptor type 2) on their surface.The lifetime risk was increased in: TNBC 18% for women with pathologic variants in the BRCA1 gene, 10% for mutations in the PALB2 gene, 7% for BARD1, 6% for BRCA2, and 5% for RAD51D.
Age – the older the age, the higher the risk; at age 65, the risk of developing breast cancer in the next 10 years is 3.5
Hormonal factors
- The number of years in a woman’s life when she is under the influence of estrogens and progestins, especially the years before the first carried gravidity (pregnancy), are of crucial importance for the risk of developing breast carcinoma!
- Gravidity
  - Late first gravidity (pregnancy) – after the age of 30 – circa 3-fold increased risk.
    - Age of the woman at the first birth:
      - Birth(s) before age 30 years lowered breast cancer rates as a function of the number of children born:
        
        First child by 5.0
        
        Second child by 6.4
        
        Third child by 9.4
    - Only if the pregnancy lasted at least 34 gestational weeks was a protective effect evident.
    - Birth after 30 years of age no longer showed a protective effect.
- Childlessness – 1.5 to 2.3 times increased risk.
- High bone density
- Slenderness (high lean body weight/lean mass) at age 10 years
- Early menarche (first menstrual period before age 12)) – Thus, the risk of breast cancer is increased by 50% to 60% for women who had their menarche at age 12 compared to those who did not have their first menstrual period until age 16.
- Late menopause (timing of the last spontaneous menstrual period in a woman’s life).
- Transgender women (individuals whose gender identity is opposite to the sex assigned at birth) and who have received hormone treatment (antiandrogens and estrogens) as support to adopt female gender identity. In a cohort study, breast cancers clustered around age fifty after a median treatment duration of 18 years
High mammographic density of the glandular body.
- Tumors were detected in 6.7 per 1,000 examinations of women with dense glandular bodies and in 5.5 per 1,000 examinations of women with non-dense glandular bodies
- Also an independent risk factor for the development of contralateral breast carcinomas (+80%).
Breast carcinoma of the contralateral (“on the opposite side”) mamma – 2- to10-fold increased risk.
Socioeconomic factors – high socioeconomic status.

Behavioral causes

Nutrition
- High-fat diet – A high-fat diet with a high proportion of red meat increases, while a low-fat diet decreases the risk of breast cancer.
- Red meat, i.e. muscle meat of pork, beef, lamb, veal, mutton, horse, sheep, goat, and meat products increase the risk of breast carcinoma – Red meat is classified by the World Health Organization (WHO) as “probably carcinogenic to humans”, that is, carcinogenic. Meat and sausage products are classified as so-called “definite group 1 carcinogens” and are thus comparable (qualitatively, but not quantitatively) to the carcinogenic (cancer-causing) effect of tobacco smoking. Meat products include products whose meat component has been preserved or improved in flavor by processing methods such as salting, curing, smoking, or fermenting: Sausages, sausage products, ham, corned beef, jerky, air-dried beef, canned meat.
- High consumption of dairy products or milk (> 230 ml daily) – Adventist Health Study-2 (AHS-2) with about 52,800 participants: +22% and +50% increased risk of breast cancer, respectively).
- Foods containing acrylamide (Group 2A carcinogen) – this is metabolically activated to glycidamide, a genotoxic metabolite; an association between exposure to acrylamide and risk of estrogen receptor-positive breast cancer has been demonstrated.
- Vitamin D deficiency appears to increase the risk of developing breast cancer
- Eating dinner after 10 p.m. or just before bedtime (risk increase of 16%) versus eating dinner before 9 p.m. or eating the last meal at least 2 hours before bedtime
- Micronutrient deficiency (vital substances) – see prevention with micronutrients.
Consumption of stimulants
- Alcohol (> 10 g/day) – for every 10 g of alcohol per day, the risk of breast cancer increases by 4.2
- Tobacco (smoking, secondhand smoke – in pre-menopausal women) – That smoking increases the risk of breast cancer has been known for some time. Now a study found that passive smoking may also increase the risk of breast cancer.The researchers also observed a relationship between dose and risk of breast cancer: the more and the longer women smoked passively, the greater the increase in the risk of developing breast cancer.
Late first gravidity (pregnancy) – after the age of 30 – circa 3-fold increased risk.
Short breastfeeding period – the shorter the breastfeeding period, the higher the risk of developing breast cancer. This revealed a meta-study.
Psycho-social situation
- Shift work or night work (+32%) [35, especially the alternation of early, late, and night shifts; may not apply to regular night work – according to the International Agency for Research on Cancer (IARC) assessment, shift work is considered “probably carcinogenic” (group 2A carcinogen)
- Sleep duration < 6 h and > 9 h is associated with an increased risk of breast carcinoma
Overweight (BMI ≥ 25; obesity).
- A five kg/m2 increase in BMI in postmenopause increases risk by a relative 12%. For premenopausal breast carcinoma, there is a negative association
- Breast cancer patients who are overweight or obese are more likely to suffer from a more aggressive tumor and have lower survival than patients with normal weight.
- Increased BMI at diagnosis of breast carcinoma is associated with increased all-cause mortality.
Android body fat distribution, that is, abdominal/visceral, truncal, central body fat (apple type) – there is a high waist circumference or an increased waist-to-hip ratio (THQ; waist-to-hip ratio (WHR)); increased abdominal fat is a risk factor for postmenopausal breast carcinoma and is associated with an increased risk of estrogen receptor-negative breast carcinomaWhen waist circumference is measured according to the International Diabetes Federation guideline (IDF, 2005), the following standard values apply:
- Women <80 cm
In 2006, the German Obesity Society published somewhat more moderate figures for waist circumference: < 88 cm for women.

Disease-related causes

Diabetes mellitus type II
Mastopathy – most common breast disease between the ages of 35 and 50, is associated with cystic or fine or coarse nodular changes in breast tissue. Hyperestrogenism is thought to be the cause.
- The risk of breast cancer is increased by a factor of approximately 2 in mastopathy
- Regardless of familial factors, breast cancer risk is increased by approximately one-third in women with benign findings.
Periodontitis -14% increased risk; this is especially true for women with periodontitis who had quit smoking in the past 20 years (36% increased risk).
Premalignant changes (ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS)) can progress to invasive carcinoma. It is estimated that over a 10-20 year period, approximately 50% of these changes become malignant.
Women who had Hodgkin’s disease in their youth (8-18 years) and whose chest wall was irradiated involving the mammae have a high risk of developing breast carcinoma after 15-30 years (17,18)

Medication

Calcium antagonists: long-term therapy >10 years increases the risk of ductal and lobular breast carcinomas
Ovulation inhibitors:
- The use of hormonal contraceptives, in contrast to the protective effect on the development of endometrial and ovarian cancer (endometrial and ovarian cancer), increases the risk of developing breast cancer by a factor of 1.2 to 1.5 when taken for more than five years [2,14]. 5-10 years after stopping ovulation inhibitors (birth control pills), this effect is no longer detectable.
- The risk of breast cancer increases with duration of use, according to a population-based study, normalizing within 5 years after cessation of hormonal contraception: the relative risk was 1.20 and was statistically significant with a 95 percent confidence interval of 1.14 to 1.26; the relative risk increased from 1.09 (0.96-1.23) for a duration of use of less than one year to 1.38 (1.26-1.51) for a duration of use of more than 10 years.
Hormone replacement therapy (HRT):
- There is a slight increase in breast cancer rates under hormone replacement therapy . After a period of use of more than five years, the risk of breast cancer increases by less than 0.1% per year (<1.0 per 1,000 women per year of use). However, this applies only to combination therapy (estrogen-progestin therapy), not to isolated estrogen therapy. For estrogen-only therapy, the median risk was actually lowered after a median duration of use of 5.9 years. Furthermore, when discussing the risk of breast carcinoma, it must be taken into account that hormone application is not responsible for the development of breast carcinoma, i.e., it does not have an oncogenic effect, but merely accelerates the growth of hormone receptor-positive carcinomas. Note: However, the increase in risk is lower than that due to regular alcohol consumption and obesity.
- Meta-analysis confirms breast cancer risks. Here, type of therapy, duration of treatment and body mass index (BMI) are important influencing factors. The following are the most important findings in this regard:
  - More often developed breast cancer women who began hormone therapy after menopause; the risk was also detectable for monopreparations, although the risk was significantly higher for users of combination preparations.
  - Type of therapy
    - Primarily, the incidence of estrogen receptor-positive breast cancer is increased. Breast cancer risk increases with BMI because estrogens are known to be produced in adipose tissue. Regardless, the added risk from estrogens was greater in lean women than in obese women.
    - Use of combined hormone preparations led to 8.3 cases of breast cancer per 100 women in women 50 years of age and older after more than 5 years of use (women who never took hormones and were between 50 and 69 years of age had 6.3 cases of breast cancer per 100 women), i.e., use of combined hormone preparations leads to one additional breast cancer in 50 users.
      - When estrogens combined with intermittent progestin are taken, 7.7 per 100 users develop breast cancer, i.e., taking them leads to an additional breast cancer in 70 users.
    - Taking estrogen monopreparations resulted in 6, 8 cases of breast cancer per 100 women (women who never took hormones and were between 50 and 69 years of age had 6.3 cases of breast cancer per 100 women) after more than 5 years of use, which means one additional cancer for every 200 users.
  - Treatment duration
    - 1-4 years: relative risk of
      - 1.60 for estrogen-progestin combinations.
      - 1.17 for estrogen-monopreparations
    - 5 -14 years: relative risk of
      - 2.08 for estrogen-progestin combinations.
      - 1.33 for estrogen-monopreparations
  - Age of the user at the time of the start of treatment.
    - 45-49 years of age: relative risk of
      - 1.39 for estrogen monopreparations.
      - 2.14 for estrogen-progestin combinations
    - 60-69 years of age: relative risk of.
      - 1.08 for estrogen monopreparations.
      - 1.75 for estrogen-progestin combinations
  - Estrogen receptor-positive tumors (frequency related to duration of use).
    - Intake 5 to 14 years: relative risk of
      - 1.45 for estrogen monopreparations.
      - 1.42 for estrogen-progestin combinations
  - Estrogen receptor-negative tumors
    - Intake 5 to 14 years: relative risk of.
      - 1.25 for estrogen monopreparations.
      - 2.44 for estrogen-progestin combinations
  - Varia: For estrogen-only preparations, there was no heterogeneity of risk between equine estrogen and estradiol or between oral administration and transdermal administration.
- CONCLUSION: A careful risk-benefit assessment must be made when hormone replacement therapy is used.

X-rays

Exposure to ionizing radiation (see Hodgkin’s disease above).

Environmental exposures – intoxications (poisonings).

Aluminum?
Dichlorodiphenyltrichloroethane (DDT) – insecticide banned in early 1970s; even prenatal exposure is associated with increased risk of breast cancer: Women in the top third of exposure showed an odds ratio of 5.42, with a wide 95% confidence interval of 1.71 to 17.19, however; women who did not develop breast cancer until after menopause (menopause), aged 50 to 54 years, showed a dose-dependent increase in breast cancer risk; in the top third of exposure, the odds ratio was 2.17 (1.13 to 4.19)
Hair dye
- Permanent hair dyes and chemical hair straighteners (risk increase for African American women: 45% if such products were used at least once within the preceding 12 months; 60% if dyeing was done every five to eight weeks; risk increases for white participants, however, were only 7% and 8%, respectively)
- Cumulative increased risk of estrogen receptor-negative breast cancer, progesterone receptor-negative breast cancer.
High nighttime exposure to LED light both indoors and outdoors – highest light exposure was associated with a nearly 1.5-fold increased rate of breast cancer
Polychlorinated biphenyls* (PCBs).
Polychlorinated dioxin*

* Belongs to the endocrine disruptors (synonym: xenohormones), which even in the smallest amounts can damage health by altering the hormonal system. Further

Trans men, although mastectomized, can also develop breast cancer.Note: A mastectomy is the surgical removal of breast tissue.