BRCA 1 and 2: Breast and Ovarian Cancer Susceptibility

BRCA1 and BRCA2

• BRCA1 located on chromosome 17 and BRCA2 on chromosome 13; both exhibit autosomal recessive inheritance.
• Increased familial risk of breast and ovarian cancer due to inherited mutations.
• Individual lifetime risk for breast cancer is 50-80% and for ovarian cancer 30-50%.
• BRCA proteins are critical for DNA repair mechanisms, particularly in addressing double-strand breaks.

PTEN and Tumor Suppression

• PTEN gene encodes a phosphatase that dephosphorylates PIP3 to PIP2, antagonizing PI3 kinase activity.
• Loss of PTEN leads to unregulated cell proliferation and potential carcinogenesis.
• Germline mutations in PTEN are linked to Cowden syndrome, presenting growths and increased cancer risk, including breast, prostate, and thyroid cancers.

p53 and Cell Cycle Regulation

• p53 is a vital tumor suppressor that regulates the expression of over 50 genes involved in the cell cycle and apoptosis.
• Normal function requires binding with Mdm2; phosphorylation alters this interaction, allowing p53 accumulation.
• p21, mediated by p53, inhibits Cyclin D/Cdk4 to pause the cell cycle at the G1/S checkpoint for DNA repair.

p53 in Apoptosis and Angiogenesis

• p53 facilitates the expression of pro-apoptotic genes and can induce cellular apoptosis after extensive DNA damage.
• The activation of caspases leads to apoptotic cell death; mutations in the p53 gene can hinder this pathway.
• p53 also regulates genes that inhibit angiogenesis, such as thrombospondin.

p53 Gene Mutations

• Most mutations in the p53 gene are missense mutations affecting the DNA binding domain, leading to loss of function.
• Li-Fraumeni syndrome is characterized by inherited p53 mutations, resulting in a 25x increased cancer risk by age 50.
• Some mutations may create dominant negative effects, impairing wild-type p53 function.

Viral Interference with Tumor Suppressors

• Oncogenic viruses, like HPV, produce proteins that inhibit tumor suppressor proteins; HPV E7 inactivates Rb and E6 inactivates p53.
• E6 and E7 facilitate cell proliferation and contribute to cancer development.

Cancer Treatment Approaches

• Conventional treatments include surgery, radiotherapy, and chemotherapy; newer molecular therapies are emerging.
• Surgical excision is often combined with other treatments to target remaining cancer cells or metastases.
• Radiotherapy aims to induce DNA damage; however, it can also affect rapidly dividing normal cells.

Tumor Sensitivity to Therapy

• Tumor heterogeneity leads to varying sensitivity to treatments based on cell type, proximity to blood supply, and mutations.
• Chemotherapy aims for maximum efficacy with minimal side effects; the therapeutic index assesses the safety of drugs.

Chemotherapeutic Agents and Clinical Trials

• Chemotherapy disrupts DNA, RNA, and protein functions to induce apoptosis, though it can also affect normal proliferating cells.
• Drug testing progresses through multiple phases, including cell culture, animal models, and clinical trials (Phase I-III), evaluating efficacy and safety.

Learn about the BRCA 1 and 2 genes, their role in breast and ovarian cancer susceptibility, and the risks associated with inherited mutations. Understand the autosomal recessive inheritance pattern and the individual lifetime risk of cancer.