Breast cancer - molecular biology and genetics

This page presents information on the molecular biology and genetics of breast cancer.

Intense research into the genetic basis of familial breast cancer led in the 1990s to the identification of the 'high risk' breast cancer susceptibility genes BRCA1 and BRCA2. 1, 2 However, faults in these genes are rare, and account for only a minority of familial breast cancer.

Most breast cancer families probably carry faults in one or more moderate or low-risk genes, and attention has shifted towards identifying these genes. Inheriting a faulty version of the gene CHEK2 may double a woman's risk, and alteration of CHEK2 may be involved in a substantial proportion of families with two cases of breast cancer. 3, 4

Most cases of breast cancer are 'sporadic' not familial, and are caused by gene damage acquired to breast cells during the woman's lifetime ('somatic' mutations). A wide variety of genes are commonly mutated or incorrectly regulated in sporadic breast cancers and have been implicated in the development and progression of the disease. These include genes encoding growth factors and receptors, intracellular signaling molecules, cell cycle regulators, apoptosis (cell death) regulators, and adhesion molecules.

Studies of these altered molecules are identifying new diagnostic and prognostic markers and unearthing new potential targets for therapy.

Back to top ^

The most frequent alterations include:

• overexpression of the epidermal growth factor receptors EGFR, HER-2/neu, ERBB3 and ERBB4;
• amplification of the MYC gene;
• mutation and overexpression of the intracellular signaling molecules h-Ras and c-Src;
• mutation and inactivation through other means of the cell cycle regulators p53 and RB1;
• overexpression of cyclin D1;
• reduced expression of the adhesion molecule E-cadherin

Recently a link was established between sporadic and inherited breast cancers with the discovery that the EMSY gene is amplified in a proportion of sporadic breast cancers. The EMSY gene codes for a protein that interacts with a highly conserved region of the BRCA2 protein, providing evidence for a shared disease pathway. 5

Amplification of the EMSY gene is also associated with a poor prognosis, indicating that this gene could also be a useful marker of disease severity.

The risk of acquiring the gene damage that causes breast cancer may itself be influenced by a woman's genetic makeup. Variant forms (polymorphisms) of many different genes, for example those involved in detoxifying environmental carcinogens, may be associated with a slightly increased (or decreased) risk of breast cancer. 6

A woman's overall risk is likely to be influenced by the precise combination of such low-risk gene variants that she has inherited.

Back to top ^