Breast cancer and genetics

• ALSO KNOWN AS: Ductal carcinoma; lobular carcinoma

DEFINITION: Approximately one in eight women develops breast cancer over the course of her lifetime. Breastcancer.org estimated that 310,720 new cases of breast cancer would be diagnosed in women and 2,800 new cases in men in the United States in 2024. More than forty different genes have been found to be altered in breast cancers. It is estimated that about 5 to 10 percent of all breast cancers can be attributed to inherited gene mutations. Approximately 80 to 85 percent of these can be attributed to mutations in the BRCA1 or BRCA2 gene. Other gene mutations associated with a high risk of breast cancer include TP53, PTEN, STKII/LKB1, and CDH1. Genes associated with a low-to-moderate risk of breast cancer include ATM and CHEK2. Each of these gene mutations is associated with a different disease or syndrome. BRCA1 and BRCA2 are associated with hereditary breast and ovarian cancer; TP53 and CHEK2 with Li-Fraumeni syndrome, PTEN with Cowden’s disease, STKII/LKB1 with Peutz-Jeghers syndrome, CDH1 with hereditary diffuse gastric carcinoma syndrome, and ATM with ataxia telangiectasia.

Risk Factors

Female gender and increasing age are considered risk factors for breast cancer. Modifiable risks include lifestyle choices that effect exposure to endogenous estrogens or environmental toxins. Family history of breast cancer is also a risk factor.

Etiology and Genetics

The BRCA1 gene is located on chromosome 17q21 and encodes a protein that is 1,863 amino acids long. Germ-line mutations of BRCA1 are associated with 50 percent of hereditary breast cancers and with an increased risk of ovarian cancer.

The BRCA2 gene is on chromosome 13q12-13 and encodes a protein of 3,418 amino acids. Germ-line mutations of BRCA2 are thought to account for approximately 35 percent of families with multiple-case, early onset female breast cancer. Mutations of BRCA2 are also associated with an increased risk of male breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer.

Although BRCA1 was cloned in 1994 and BRCA2 in 1995, the function of these genes has been difficult to identify. Part of the difficulty has been that the proteins coded by these genes do not resemble any proteins of known function. In 1997, David Livingston and coworkers of the Dana-Farber Cancer Institute found that the BRCA1 gene product associates with repair protein RAD51. A few months later, Allan Bradley of Baylor College of Medicine and Paul Hasty of Lexicon Genetics reported that the BRCA2 protein binds to the RAD51 repair protein. This work suggests that both genes may be in the same DNA-repair pathway. Bradley and Hasty also showed that embryonic mouse cells with inactivated mouse BRCA2 genes are unable to survive radiation damage, again suggesting that the BRCA genes are DNA-repair genes. Initially, it was thought that the breast cancer genes were typical tumor-suppressor genes that normally function to control cell growth. The 1997 work suggests that the breast cancer gene mutations act indirectly to disrupt DNA repair and allow cells to accumulate mutations, including mutations that allow cancer development. In 2002, the detailed structure of the BRCA2 protein was determined. It has structural motifs that show it to be capable of binding to DNA. Although the specific role of the BRCA2 protein is uncertain, it is now clear that it does play a role in repairing double-stranded breaks in DNA. The understanding of the function of BRCA1 and BRCA2 is incomplete, but what is known will encourage additional studies.

The TP53 gene was the first gene identified associated with inherited breast cancer. The gene is located on chromosome 17p13.1. It is a tumor-suppressor gene that encodes a protein that stops the until DNA repair has occurred; a defective p53 protein no longer stops cell division, and unrepaired DNA can be replicated, resulting in accumulated mutations in the cell. About 1 percent of women who develop breast cancer before the age of thirty have germ-line mutations in p53. Families with this syndrome have extremely high rates of brain tumors and other cancers in both children and adults.

The PTEN gene is located on 10q23.3 and is also a tumor-suppressor gene. It encodes an that modifies proteins and fats by removing phosphate groups. More than a hundred mutations in PTEN have been identified associated with Cowden syndrome. The mutation results in a defective phosphatase enzyme resulting in noncancerous growths (hamartomas) as well as cancerous tumors including breast cancer, prostate cancer, endometrial cancer, skin cancer, and brain tumors.

The STKII (serine/threonine II) gene is located at chromosome 19p13.3 and encodes a tumor-suppressor enzyme. More than 140 mutations have been identified associated with Peutz-Jeghers syndrome. The loss of this enzyme function is associated with polyps in the gastrointestinal tract that can become cancerous. This same loss of tumor-suppression function is associated with increased risk for breast cancer.

The CDH1 gene is located on chromosome 16q22.1 and encodes an epithelial cadherin protein. E-cadherin helps cells stick together. An inherited mutation in CDH1 increases the risk of cancer of the milk-producing glands associated with hereditary diffuse gastric cancer (HDGC).

There is an increased incidence of breast cancer associated with the AT (ataxia telangiectasia) gene and the HRAS1 gene. A mutated form of the gene, called ATM (ataxia telangiectasia mutated), is located on chromosome 11q22-23 and codes for a serine/threonine-specific protein kinase that plays a role in DNA damage repair. The ATM gene is found in the rare recessive hereditary disorder ataxia telangiectasia, which has a very wide range of symptoms, including cerebellar degeneration, immunodeficiency, balance disorder, high risk of blood cancers, extreme sensitivity to ionizing radiation, and an increased risk of breast cancer. Individuals with one mutated copy of the ATM gene have an increased risk of cancer. The ATM gene was identified as a phosphatidylinositol-3 kinase (an enzyme that adds a phosphate group to a lipid molecule) that transmits growth signals and other signals from the cell membrane to the cell interior. The ATM gene was found to be similar in sequence to other genes that are known to have a role in blocking the cell cycle in cells whose DNA is damaged by ultraviolet light or X-rays. It is possible that the mutated ATM gene does not stop the cell from dividing, and the damaged DNA may lead to cancers. It is disturbing to note that individuals with a mutated ATM gene may be more sensitive to ionizing radiation and should therefore avoid low x-ray doses, such as those received from a mammogram used to detect the early stages of breast cancer.

Screening and Diagnosis

A simple blood test can check for BRCA1 and BRCA2 mutations. Such testing has been controversial, however, raising a number of social and psychological issues. There is a concern that the technical ability to test for genetic conditions is ahead of the ability to predict outcomes or risks, prescribe the most effective treatment, or counsel individuals. Part of the dilemma about testing is the uncertainty about the meaning of the test results. If a test confirms the presence of a mutation in a breast cancer gene in a woman with a family history of breast cancer, then there is a high risk—but not a certainty—that the woman will develop breast cancer. Even if a test is negative, it does not mean the woman is not at risk for breast cancer because the large majority of breast cancers are not inherited. If a test is positive, then it is not clear what the best course for the woman would be. Increased monitoring with mammography and even removal of both breasts as a preventive measure should reduce the chances of developing cancer but do not guarantee a cancer-free life. Even if a woman does not yet have cancer, she may feel the additional psychological stress of knowing she has a high risk of developing it.

There is also concern that test results may be misused by employers or insurers. A number of states have passed laws that prevent health insurance companies from using genetic test results to discriminate against patients. In 2008, the federal government passed the Genetic Information Nondiscrimination Act (GINA), which prohibits discrimination based on genetic information by employers and insurance companies with the exception of life insurance, disability insurance, and long-term care insurance. In 1996, the National Cancer Institute established the Cancer Genetics Network as a means for individuals with a family history of cancer to enroll in research studies and learn of their genetic status while receiving counseling.

In 2024, researchers from Stanford University published study results describing new ways to interpret gene variants related to breast cancer. They reported that it was possible to study the germline genome inherited and present at birth to determine not only the presence of genetic conditions that predispose a person to breast cancer, but also the type of cancer they might develop and its likely severity. They suggested this new understanding could make genetic testing for breast cancer more helpful and eliminate some of the concerns associated with it.

Symptoms

The symptoms of hereditary breast cancer are similar to somatic breast cancer: a lump or thickening in the breast or lymph nodes under the armpits; change in the size, shape, or feel of the breast or nipple; discharge from the nipple.

Treatment and Therapy

Treatment for hereditary breast cancer is similar to somatic breast cancer. It depends on the type and stage of the cancer, and if it is hormone-sensitive estrogen receptor (ER) positive or human epidermal growth factor receptor 2 (HER2) positive.

Prevention and Outcomes

Some patients want to reduce their risk of breast cancer and choose to have preventive or prophylactic treatment. Cancer screening is a way to detect breast cancer early, when it may be easier to treat. Mammography and clinical breast exams are two common screening methods. Magnetic resonance imaging (MRI) is also used. Prophylactic surgery is a preventive option. Bilateral prophylactic mastectomy (removal of healthy breasts) or prophylactic salpingo-oophorectomy (removal of healthy Fallopian tubes and ovaries) are two options. Some women choose to have both procedures. Chemoprevention is another strategy. Two drugs have been approved for this use: tamoxifen and raloxifene. Tamoxifen has been shown to reduce the risk of breast cancer in premenopausal and postmenopausal women. Raloxifene is approved for use in postmenopausal women.

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