Carcinogenesis: Cancer suppressor oncogenes

1. General

   1. protein products apply brakes to cellular proliferation

   2. suppress tumor formation by regulating cell growth

2. Molecules that regulate nuclear transcription and cell cycle

   1. Rb—restinoblastoma gene

      1. normal

         1. a nuclear phosphoprotein that regulates cell cycle

         2. prevents cell cycle from going from G1 to S phase

      2. mutated

         1. when protein absent due to mutation, brakes on cell cycle lifted

         2. cell divided unregulated

      3. genetic

         1. in familial case, children are born with one defective copy and lose the other thru somatic mutation

   2. p53

      1. General

         1. single most common target for genetic mutation in tumors

         2. in most, inactivation of both alleles

         3. Li-Fraumeni syndrome

            1. Rare clinical syndrome where patient inherits one mutant alleles and only needs “one hit” to inactivate 2^nd allele

      2. Characteristics of p53—guardian of genome

         1. Acts in nucleus

         2. Causes cells to arrest in G1 by inducing inhibitor of CDK

            1. This prevents cyclin/CDK complex to form

            2. Prevents cell from entering S phase

         3. Allows time to repair DNA

         4. Also induces DNA repair enzymes

         5. If DNA cannot be repaired, p52 causes cell to undergo apoptosis

      3. Mutation

         1. homologous loss of p53 results in ultimate malignant transformation

         2. normal p52 can be made non-functional by certain viruses

   3. BRCA-1 and BRCA-2 genes

      1. general

         1. newly discovered tumor suppressor genes

      2. norm: secreted from breast epithelium and involved in trascription regulation

      3. mutations: cause  risk of breast/ovarian cancers

      4. important in hereditary BC

3. Molecules that regulate SIGNAL TRANSDUCTION

   1. general

      1. cause down regulation of growth promoting signals

   2. adenomatous polyposis coli (APC)

      1. both copies of gene need to be lost for tumor to develop

      2. if born with one mutant allele,

         1. patient develops numerous polyps, some of which become malignant due to loss of 2^nd allele thru somatic mutation

      3. APC protein normally controls level of beta-catenin which activated growth promoting genes

      4. when APC is lost, levels of beta-catenin are not controlled and abnormal cellular growth can occur

   3. NF-1 gene

      1. product is neurofibromin

      2. normal gene

         1. encodes GTPase activating protein that facilitates conversion of active ras to inactive ras

      3. mutation

         1. if lose NF-1, ras may stay active

      4. if inherit one mutant allele

         1. get neurofibromas that may progress to neurofribrosarcomas

Category: Pathology Notes