Cancer is a term used to describe a group of diseases involving unregulated cell growth. In cancer diseases, cells multiply uncontrollably, thereby creating malignant tumors that spread into other parts of the body. Please note that cancer and the word tumor are not the same. A tumor can be either benign or malignant. Benign tumors are tumors that do not invade other parts of the body; they are localized in a specific organ and usually have a much better prognosis. On the other hand, malignant tumors are dangerous because they have the capability to spread to and invade other organs. They can enter the bloodstream or the lymphatic system and distally spread to other parts of the body; this process is also called metastasis. For example, it is common for breast cancer to metastasize into other parts of the body including axillary lymph nodes, the lungs, and the brain.

Tumor suppressors and Oncogenes

Think of tumor suppressors as the brakes that prevent cancer development and oncogenes as the gas pedal that accelerates cancer development. There are several functions of tumor suppressor genes, such as ensuring the cell cycle controls and checkpoints, repairing DNA damage, promoting apoptosis, and preventing epithelial to mesenchymal transitions (EMT). When the tumor suppressor genes are inactivated, these functions are impaired and can result in cells containing damaged DNA to proliferate uncontrollably, thereby forming tumors and eventually metastasizing to other parts of the body. There are several ways in which tumor suppressor genes can be deactivated, such as through epigenetic regulation (promoter hypermethylation), gene deletion, or mutations resulting in protein truncation. Most tumor suppressors are recessive, and both alleles need to be inactivated for the phenotype to appear. With only one of the alleles still active, this tumor suppressor gene can still perform its functions. BRCA1 and BRCA2 are tumor suppressors, along with many other examples such as P53, PTEN, RB, APC, and others.

Oncogenes, on the other hand, are dominant; mutation in only one of the alleles is sufficient to make cells evade apoptosis and continue proliferating. In cancer, proto-oncogenes can be mutated, resulting in gain of function. When a proto-oncogene is activated, it is then referred to as an oncogene. Oncogenes can be activated by several ways, including mutation, epigenetic regulation, chromosomal translocation, or gene duplication. The result is hyperactive or highly expressed oncogenes that overcome the functions of tumor suppressor genes and promote cancer development. Examples of oncogenes include MYC, RAS, TGF-B, HER2, ERK, and others.

Sporadic vs. heritable cancer

Cancer is a genetic disease that is caused by aberrations in the DNA. This also means that the aberrations can be passed on from the parents to their offspring, resulting in a heritable cancer. These individuals are born with one defected allele that is inherited from one of their parents. Defected tumor suppressors are more commonly inherited than oncogenes. For tumor suppressors, both alleles need to be nonfunctional for cancer to develop. This was first explained by Alfred G. Knudson in 1971 with Knudson’s two-hit hypothesis. Alfred used retinoblastoma (a cancer that develops in the retina) that occurs in very young children. He then discovered that these children inherited a defective tumor suppressor gene called RB1 from one of their parents. The first hit refers to the defect that is inherited, and the second hit is an event that occurs during life. This could be due to random mutations that occur during cell division or upon an external factor, such as sun radiation that results in inactivation of the second allele. Because these individuals already have the first hit, they develop cancer at a much earlier age than other individuals who are born with both healthy alleles because these individuals need to acquire both hits during their life (Figure 1)

Figure 1. Illustration of Knudson’s two-hit hypothesis of tumor suppressor inactivation in familial(hereditable) cancer. 10 Knudson, A.G. (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 68, 820-823,PubMed.

Diagram illustrating tumor suppression gene inactivation in a normal cell versus a cell with a germline mutation. The normal cell starts with two wild type copies of the tumor suppression gene, or TGS. Then a mutation occurs affecting one copy of the TSG. After some time has passed, a second mutation occurs that inactivated the second copy of TSG, leading to tumor formation. In the cell with germline mutation, the starting point is one copy of TSG with a mutation and one wild type copy. The second hit affects the inactivates the wild type copy, leading to tumor formation earlier than in the normal cell.


  1. Knudson AG Jr., 1971, Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. Apr;68(4):820-3.


Breast cancer

Theory overview