Carcinogenesis: Growth promoting oncogenes

Growth factor receptors

1. Oncogenes may cause mutant receptor proteins

   1. mutant receptor delivers continuous mitogenic signals even in absence of growth factors

2. Over-expression of receptors

   1. more common

   2. c-erb B-2 (Her2 neu)

      1. a mutant version of EGF receptor that is amplified 15-30% in breast cancers and other adenocarcinomas

      2. Herceptin—drug that blocks receptor, inhibits growth

         1. used to treat metastatic BC

3. Signal transducing proteins

   1. Ras

      1. Many tumors have mutations in ras gene

      2. Normal state

         1. bind GTP/GDP

         2. converts from active to inactive state

         3. in inactive state, binds GDP

         4. when activated binds GTP—results in cell proliferation

         5. normal protein has short half-life

            1. hydrolyzes GTP and releases Pi and becomes inactive (bound to GDP)

         6. GAP (GTPase activating proteins) act as brakes for ras by hydrolyzing GTP

      3. Muatated ras

         1. bind GAPs and prevent them from hydrolyzing GTP

         2. mutant ras proteins trapped in active state (bound to GTP)

         3. cell continues to proliferate

   2. c-able protooncogene

      1. normal

         1. encodes a plasma membrane associated signal transducer protein that links external growth factors to cell proliferation

         2. normally found on chromosome #9 and is regulated there

      2. mutant

         1. when translocated to chromosome #22 (as in chronic myelogenous leukemia-CML) regulation is lost

         2. hydrid gene between c-abl and break point cluster (bcr) of chromosome #22

         3. forms bcr-c-abl gene

            1. has potent tyrosine kinase activity

            2. showers nucleus with growth promoting signals

            3. causes constant cell growth

         4. Philadelphia chromosome

            1. This translocation (9:22) is used to diagnose CML

4. Nuclear transcription factors

   1. c-myc

      1. MOST COMMON in tumors

      2. Normal

         1. binds DNA causing activation of transcription of several growth related proteins

            1. especially cyclin D1

         2. when cell cycle begins, myc levels decline to near basal level—growth is slowed

      3. mutant

         1. associated with persistent expression or over-expression

         2. as a result of chromosomal translocation (8:14) there is dysregulation of myc

            1. seen in Burkitt’s lymphoma

5. Cyclins/CDK’s

   1. normal

      1. various phases of cell cycle controlled by CDK after they are activated by cyclins

   2. mutations

      1. dysregulation of expression of D cyclin results in cells constant progession into S phase

      2. common even in neoplastic transformation

      3. over-expression of cyclin D associated with a variety of cancers, especially LYMPHOMAS