Hereditary Breast Cancer Signaling

Breast cancer is the second most common type of cancer worldwide. 5%-10% of breast cancer cases are estimated to fall into the class of hereditary breast cancer, which is characterized by an inherited susceptibility to breast cancer due to mutations in high enetrance susceptibility gene(s) including BRCA1, BRCA2, CHK2, p53 and PTEN.BRCA1 and BRCA2 are two of the best studied genes in breast cancer. BRCA1 is a multi-factorial protein with a significant role in a number of cellular processes. It is involved in: 1) DNA damage response where BRCA1 is phosphorylated by damage sensors like ATM and ATR. BRCA1 can also be phosphorylated by CHK2; CHK2 is itself implicated as a susceptibility gene in hereditary breast cancer. BRCA1 controls downstream molecules of the G2/M cell cycle checkpoint. Mutations in BRCA1 render this function void. 2) DNA repair - BRCA1 participates in homologous recombination during meiosis and repair of double strand breaks. It is also involved in non-homologous end-joining. BRCA1 associates with a number of complexes like BASC, MRN and BRCA2-RAD51 to mediate DNA repair. 3) Ubiquitination - BRCA1 forms an E3 ubiquitin ligase along with BARD1 and monoubiquitinates proteins like RNAPII and H2AX thereby regulating chromosome stability and DNA repair. 4) Transcriptional regulation - BRCA1 regulates the expression of various genes, either directly or by associating with other transcriptional regulators thereby controlling several biological processes such as the cell cycle and DNA excision repair.PTEN and p53 are two important tumor suppressors mutated in the hereditary form of breast cancer. Under normal cellular conditions, p53 regulates target genes that induce cell cycle arrest and apoptosis. PTEN is a PIP3 phosphatase and functions as a tumor suppressor by negatively regulating AKT/PKB signaling. Mutations in either of these genes results in the loss of critical regulatory functions in the cell leading to increased tumorigenesis. Thus mutations in one or several of the susceptibility genes affects normal cell function leading to increased tumorigenesis.