One of the essential parts of treating disease is understanding the etiology. Through the comprehension of disease, many therapeutic targets are developed. However, often we do not know what exactly causes disease and only comprehend partially the pathogenesis of the disease. An example of this is breast cancer.
Breast cancer is one of the most common types of cancer in women. Like other types of cancers, it is a heterogeneous disease than can be classified in several ways. The most common of these is through histological or molecular subtypes. Even though in some particular cases the causes of breast cancer can correspond to a particular clinical subtype of cancer, often this is not the case. Additionally, in most cases of breast cancer, no specific cause can be identified.
What Causes Breast Cancer?
Current understanding of the causes of breast cancer has been the product of integrating the general mechanism, by which all cancer originates from, with the specific causes of breast cancer. Therefore, in order to understand what causes breast cancer, one must first understand the general process of carcinogenesis and the associated characteristics resulting from it. After this, one must integrate the currently known risk factors for breast cancer with this process.
Carcinogenesis is the process by which regular cells become malignant cells. This process is often multifactorial and of great complexity. This complexity arises from the numerous causes and interactions between these causes. In general, the causes of cancers are classified as exogenous, endogenous or genetic.
The exogenous causes of cancers are labeled as carcinogens due to their capacity to induce carcinogenesis in cells. The World Health Organization classifies carcinogens according to their nature into three groups, chemical, physical and biological. Even though there is strong epidemiological about almost all known carcinogens, the mechanism by which they produce cancer is unknown.
Chemicals, like the other two groups, are a varied group of carcinogens originating from diverse sources and with great differences in their structure. Chemical carcinogens include both inorganic compounds (such as nickel, cadmium, and arsenic) and organic compounds (such as nitrosamines or trichloroethylene). The mechanisms by which they produce cellular lesions are incredibly diverse. Additionally, a single chemical compound can produce lesion through several disruptions. Hormones and hormone-like compounds are known as chemical causes of breast cancer. Interacting directly with some breast cancer through estrogen receptors or through the stimulation of inflammatory pathways. Recently, evidence for the role of estrogen receptors has been found in the increased risk of breast cancer in patients with hormonal therapy.
Another group of carcinogens includes physical agents. Physical forces can also have a tremendous effect on cells, which can later result in cancer. Among the physical carcinogens are ultraviolet radiation, iatrogenic sources of radiation and radiation from materials such as uranium. Physical agents are also candidates participating in the multifactorial cause of breast cancer. Specifically, iatrogenic radiation has been linked to increased risk of breast cancer.
The last group of exogenous carcinogens is the biological group. These include several viruses and bacteria that act as carcinogens in mankind. Among these are the human papilloma virus (HPV16 and HPV18), human herpes virus 8, the Epstein-Barr virus and Helicobacter pylori. Biological causes are associated with numerous cancers such as cervical cancer, Kaposi sarcoma, lymphomas, and gastric cancer. But, their role in breast cancer has not been documented.
Carcinogens are not only exogenous but can also emerge from a process within the body. These carcinogens are labeled, in contrast, endogenous. However, whether endogenous carcinogens are considered true causes of cancer is subject to debate because they act as mediators of exogenous carcinogens. Nevertheless, their role in the development of cancer is essential. Among the endogenous carcinogens are the reactive oxygen species and inflammatory mediators. These trigger numerous responses in the body that can lead to cancer development. For example, breast cancer has been linked to many diseases characterized by an increased inflammatory state such as obesity or type 2 diabetes.
Often, in cancer, the exogenous and endogenous carcinogens interact with the genetic makeup of patients. The process by which genes interact has been well described in scientific literature. Cancer is essentially a genetic disease, but not in the traditional description. Cancer cells are characterized by damage to its genetic material but most of this damage is not the product of mutation in the germline. Cancer, in contrast, is the result of somatic mutations that accumulate in certain cells. This can be observed in cancer where 80 to 90% of cases of breast cancer are not explained by hereditary factors. This does not exclude the effect of inherited mutations that can lead to the remaining 10 to 20% of cases of breast cancer. Regardless of the predominance of environmental causes, inherited mutations need to be considered.
The mutations, either somatic or inherited, associated with the development of cancer are restricted to a few particular types of genes. These are labeled as cancer genes and include tumor suppressor genes, oncogenes, DNA repair and checkpoint genes, risk modulating genes and execution genes.
As a result of the complex interaction between the carcinogens and the genes associated with the cancerous process, cancer cells are created. These cells will have some characteristics and behavior which allow it to grow and later metastasize. These characteristics were summarized in the year 2000 by Hanahan and Weinberg as the Hallmarks of Cancer. The six classical hallmarks are resisting cell death, sustaining proliferative signaling, evading growth suppressors, inducing angiogenesis, enabling replicative immortality and activating invasion and metastasis. As a result of recent discoveries additional hallmarks are currently being proposed, such as the evasion of immune destruction and the dysregulation of cellular energetics. All of these, also have a role in explaining how to do the interactions between the genetic alterations and carcinogens cause breast cancer.
Most of the previous causes and process are can be observed as the specific causes of breast cancer. These, like for other cancers, can be classified into genetic and environmental causes.
The genetic causes of breast causes include various mutations in genes that result in different increases in the patient’s risk of breast cancer. An inverse relationship with the risk of cancer to the frequency of the mutation. Due to these differences genes can be grouped as common (low risk) genes, rare (moderate risk) genes, and very rare (high risk) genes.
The group of the high-risk genetic causes of breast cancer is one of the most researched and known mutations involved in breast cancer. The most common and representative mutations occur in the BRCA1 and BRCA2. The name of these genes originates from their role in breast cancer (BR + CA). These high-risk mutations are including some of the known hereditary breast cancers. But, in sporadic cases of breast cancer mutations in these genes are also observed. The BRCA1 and BRCA2 are examples of tumor suppressor genes involved in DNA repair and control of homologous recombination. As a result, BRCA1 and BRCA2 mutations are associated with genetic instability and dysregulation of cell replication which can cause breast cancer.
The protein coded by the BRCA2 gene interacts, and control numerous proteins involved in DNA repairs. These proteins are coded by genes which can cause breast cancer if mutated. These include the ATM gene, CHK genes, PALB2 gene and among others.
Germline mutations in BRCA1 and BRCA2 are associated with a 40-80% lifetime risk of breast cancer. This is a significant increase in risk when compared to the general population’s lifetime risk of breast cancer, 10%. The mutation of other genes is also associated with an increased lifetime risk of breast cancer. These include 4 breast cancer genetic syndromes, Li-Fraumeni Syndrome (P53), Cowden Syndrome (PTEN), Hereditary Diffuse Gastric Syndrome (CDH1) and Peutz-Jeghers Syndrome (STK11). As a syndrome, apart from an increased risk of breast cancer, they have other associated features, which include another type of cancers or precancerous changes.
One of the syndromes associated with hereditary causes of breast cancers is the Li-Fraumeni syndrome. Produced by the mutation of a tumor suppressor gene, TP53, a patient with this syndrome has a risk of breast cancer ranging between 50-80% by the age of 45. This gene codes for a protein that regulates gene stability in general tissues, resulting in additional risk of other types of cancers such as acute leukemia, lymphomas, and brain tumors.
Another tumor suppressor gene associated with hereditary causes of breast cancer is the CDH1 gene. Mutations in this gene cause Hereditary Diffuse Gastric Syndrome by causing dysfunction of DNA mismatch repair, causing genomic instability. This results in a 39% lifetime risk of breast cancer, specifically lobar cancer. Additionally, as seen in its name, it can also cause gastric cancers.
STK 11 is another gene associated with a breast cancer genetic syndrome, the Peutz-Jeghers syndrome. Like the previous causes of hereditary breast cancer, the STK 11 gene codes for a tumor suppressor gene. However, its mutation affects the regulation of apoptosis (resulting in evasion of apoptosis) and the use of energy. The Peutz-Jeghers syndrome represents a risk of breast cancer of 32% by the age of 60. Like the others, this syndrome also manifests as an increase in the risk of developing other cancers such as cervical adenoma malignum or lung cancer.
The Cowden Syndrome, in contrast to the previous hereditary breast cancer syndromes, is not the result of alterations of a tumor suppressor gene. Rather, it’s affected gene PTEN codes for an enzyme of the PI3K pathway. Nevertheless, it also raises the risk of breast cancer and other conditions.
The moderate risk genetic causes of breast cancer are a group composed of several genes that code for a protein involved in BRCA1 and BRCA2 functions. Some, such as the CHK genes increase the lifetime risk of breast cancer to 20-80%. Others, like the ATM gene and the PALB2 gene, increase the cancer risk in a twofold. It is important to recall that even though mutations in these genes carry a lower risk, they occur more often. Perhaps this due to the dependency of the interaction with environmental causes of breast cancers. This also occurs with the low-risk genes which include the TOX3 gene, the MAP3K1 gene, theLSP1gene, and the CASP8.
Provided that few cases are the result of hereditary causes of breast cancer and that mutation only accounts for some cases, the influence of the environment is evident in the development of breast cancer. The environmental causes of breast cancer include the exposition of patients to ionizing radiation, exposure to estrogens and a high-fat diet.
The effects of ionizing radiation and its association with cancer are evident. Through the interaction with genes, this physical cause of breast cancer can provoke genomic instability in patients. Studies have shown an increased risk of breast cancer treated with ionizing radiation associated with ATM gene mutations or independent of this gene. Additionally, it has been pointed out that excessive screening through frequent mammography can, ironically, increase the risk in patients.
Estrogen exposure has also been identified as an important risk factor in the development of breast cancer. This chemical causes of breast cancer are associated with numerous aspect of female life such as early menarche, late menopause, and fewer pregnancies. All of these can result in greater activation of receptors which stimulate proliferation pathways. Additionally, chemicals from industry, estrogen therapy or natural sources like soy have also been associated with a higher risk of breast cancer. These effects are mediated through the estrogen receptors, the structure responsible for the regulation of growth in the normal breast. More than 70% of breast cancer displays the estrogen receptor, normally along with the progesterone receptor. Estrogens additionally, through its metabolism, can produce a compound that produces reactive oxygen species. Which can either damage DNA or alter the energetically the general physiologic process in the cells?
Another environmental cause of breast cancer is a high-fat diet, a factor that interacts with many other causes. A patient with a high-fat diet, first of all, can precipitate the development of type 2 diabetes, obesity, and dyslipidemias, which are all associated with an increased in the body inflammatory mediators and reactive oxygen species. Additionally, both the direct high-fat diet and the obesity that can follow have been observed to have an estrogenic effect.
The development of cancer through the linear multi-step model can organize the causes of breast cancer in a logical manner. Initially, breast tissue is found devoid of histological changes. The only alterations could be inherited gene mutations that predispose to the disease but these require the input from environmental factors. Some of the initial environmental factors are the exposition to estrogen receptor stimulators and as consequence abnormal response in these receptors develops Additionally, as a consequence of this chemical cause of breast cancer, these cells begin to avoid apoptotic signals. Soon after this, tumor-suppressor dysfunction develops causing genetic instability and the expression of abnormal oncogenes. As a consequence, cells become cancerous cells in the breast and can behave as an in situ or invasive cancer.
This model associates both environmental and inherited causes of breast cancer to the accumulation of genetic alterations. These, in turn, can start a snowball effect of causing further instability, resulting in more genetic alterations. This can provide a logical understanding of what process and factors cause breast cancer, which allows the current physician to target some of these as pharmacological targets. Nevertheless, due to the complex nature of the causes of breast cancer, many more studies are needed to understand the diverse interaction among the causes. This way is allowing scientists and physicians to provide better treatment and prognosis to patients.