CancerQuest | Breast Cancer: Tumor Biology

Genetic changes that occur in cancer include mutation of key regulatory genes, changes in protein products, and changes in the amount of product produced by genes (gene expression). As changes accumulate, cells become more abnormal and cancer progresses. Details of genetic change associated with cancer can be found in the Mutation. Some of the genetic elements that have been shown to be important in the development of breast cancer are listed and discussed below:

BRCA1 and BRCA2 Genes
HER-2/neu Gene
Estrogen Receptor (ER)
PTEN Gene and Cowden Syndrome
TP53 Gene and Li-Fraumeni Syndrome
ATM Gene and Ataxia-Telangiectasia

BRCA1 and BRCA2

The BRCA1 and BRCA2 genes are important tumor suppressor genes associated with the repair of damaged DNA. Information about BRCA1 and BRCA2 can be found in the Cancer Genes section.

HER-2/neu

HER-2/neu is an oncogene that is amplified in up to 30% of invasive breast cancers.⁽¹⁾Information about oncogenes, gene amplification, and HER-2/neu can be found in the Cancer Genes section:

Learn more about oncogenes
Learn more about gene amplification
Learn more about HER-2/neu

Estrogen Receptor (ER)

The estrogen receptor (ER) is a protein that binds to estrogen that enters the cell. Estrogen is a steroid (lipid) hormone produced by the ovaries. The combination of protein and hormone then acts as a transcription factor to turn on genes that enable the target cells to divide. The receptor is active in the cells of the female reproductive organs, such as breasts and ovaries.

The mechanism of estrogen action is shown below.

The small green ball represents estrogen. It is a small hydrophobic molecule and it enters cells by crossing through the lipid membrane. Once in the cell, the estrogen binds to its receptor (colored orange) and the complex binds to DNA in the nucleus causing genes to be transcribed.

Several drugs have been developed to try to block the gene-activating function of estrogen. A commonly prescribed example is tamoxifen, a drug that partially inhibits the activity of estrogen. Tamoxifen is colored pink in the animation below.

These drugs should slow the growth of cancers that are growing in response to the presence of estrogen and its receptor. More information on estrogen receptors and cancer can be found in the section on cancer treatments.

PTEN Gene and Cowden Syndrome

Cowden's syndrome (CS), also known as multiple hamartoma syndrome, accounts for a small fraction (less than 1%) of hereditary breast cancers. This syndrome is caused by mutation in PTEN, a gene that functions as a tumor suppressor and helps to control the cell cycle and regulate apoptosis.

CS is also associated with abnormalities of the thyroid, gastrointestinal tract, and central nervous system.⁽²⁾ Women with CS have between a 25%-50% risk of developing breast cancer.⁽³⁾More information about tumor suppressors and the cell cycle can be found in the Cancer Genes and Cell Division sections.

Learn more about tumor suppressors
Learn more about the cell cycle

TP53 Gene and Li-Fraumeni Syndrome

Li-Fraumeni syndrome (LFS) accounts for a small fraction (less than 1%) of all breast cancer cases. This syndrome is caused by mutation in TP53 (also referred to as p53), an important tumor suppressor gene. LFS is associated with diagnosis of breast carcinoma at an early age (before age 40), as well as sarcomas, brain tumors, leukemias, and adrenocortical carcinomas.⁽³⁾

Learn more about abnormal p53 and cancer development

ATM Gene and Ataxia-Telangiectasia

Ataxia-telangectasia (AT) is a disorder caused by mutation in ATM, a tumor suppressor gene that helps to detect and repair damaged DNA.⁽⁴⁾ AT is associated with neurological (nervous system) deterioration, telangiectasias (red dots, often on the face, caused by blood vessels visible through the skin), immune deficiency, and hypersensitivity to ionizing radiation.⁽³⁾

As described in the Breast Cancer: Risk Factors, radiation exposure is a risk factor for breast cancer. Hypersensitivity to ionizing radiation caused by the ATM mutation therefore increases one's risk of developing breast cancer.

More Info on BRCA
BRCA1 and BRCA2 consist of about 17,000 bases each. This long coding sequence can make it difficult to find a single, function-altering mutation. The BRCA testing process has been separated into two stages in order to limit the complexity of the process. In the first stage, blood is drawn from the patient affected with ovarian or breast cancer. The DNA from the white blood cells is then extracted and analyzed in a laboratory to identify any BRCA mutations. In the second stage, blood is drawn from the affected patient's family members. Instead of searching through the entire gene of the family members, researchers look for the same BRCA mutation they found in the affected patient.⁽⁵⁾

BRCA mutations are responsible for 90% of hereditary ovarian cancer as well as 84% of hereditary breast cancer⁽⁶⁾. A BRCA2 mutation in men also raises the risk for male breast cancer⁽⁵⁾. These numbers may seem high, but BRCA mutations actually are uncommon in the general population. One of the highest frequencies (2%) of BRCA mutations occurs in the Ashkenazi Jewish population.

Genetic Testing for BRCA
Genetic testing can be intimidating. Genetic counselors are trained healthcare providers who help with the genetic testing process. They consult with patients in order to determine if a test is necessary and they interpret the data from a genetic test in order to better assess personal risk. They also help with the emotional and psychological impact that comes with genetic testing. Informed consent from the patient is required before any genetic testing.

Options after finding a BRCA mutation
Patients that test positive for BRCA mutation are encouraged to follow the National Comprehensive Cancer Network guidelines for breast cancer risk reduction: monthly breast self-examination, clinical breast examination semi-annually, and annual mammography and breast MRI. A prophylactic mastectomy (90-95% risk reduction) and tamoxifen (50% reduction over 5 years) are other options to reduce breast cancer risk.

Since a BRCA mutation also raises the risk of developing ovarian cancer, steps can be taken in order to reduce that risk. A prophylactic salpingo-oophorectomy reduces ovarian cancer risk by 98% and oral contraceptives reduce risk 60% over 6 years use. If prophylactic surgery is not wanted: Semi-annual pelvic exams with transvaginal ultrasound with color Doppler should begin at 35 years of age.⁽⁶⁾

HER2
HER2 tumors tend to be more aggressive, so accurate identification by a pathologist is important in determining clinical treatment. Also, studies have found that ER and HER2 interaction my lead to tamoxifen resistance. This resistance is partly due to HER2's ability to inhibit the apoptotic effects of tamoxifen. Surprisingly, HER2/EGFR signaling has been suggested to be directly involved in tamoxifen growth promotion. These factors lead to the association of tamoxifen failure with HER2 overexpression.⁽⁷⁾

PR
Progesterone regulates cell growth in normal breast tissue and in the uterus. PR plays an important role in mammary growth and development, especially during pregnanacy. PgR can up-regulate the expression of various genes involved in cell proliferation, survival, and tumor progression. PR is a predictive factor for the outcome of endocrine therapy. PR negative tumors have more aggressive features: they are larger, have more nodal metastases, are more likely to be aneuploidy and are more rapidly proliferating. Also, PgR negative tumors are associated with a significantly higher frequency of HER2 overexpression.⁽⁶⁾

ER
Recent research has indicated there are two estrogen receptors: ERα and ER². ER²'s role in normal and neoplastic breast tissue is unclear. Studies are investigating its role in breast cancer and some conclusions and suggestions have been made. A general consensus defines tumors as either ERα+/ER²+ or ERα-/ER²+. A recent study suggested that increased ER² expression was associated with a high S-phase fraction only within ERα negative patients. Data from another study suggest that ER² may be related to proliferation in breast cancer. Overall, a consistent conclusion from studies is that ERα-/ERbeta + breast tumors are positively associated with markers suggesting a more aggressive disease.⁽⁸⁾