Lecture 23 &24

• Tumor suppressor gene


  Growth limiting gene
• Differences between oncogenes and tumor suppressor genes


  • Both gene copies of tumor suppressor genes need a mutation
  • Oncogenes only need one mutation on one copy
• Cancer cells typically have mutations at

  Proto-oncogenes and tumor suppressor genes
• Gain of function at proto-oncogenes

  Induces a dominant phenotype → convert to oncogenes
• Loss of function mutations at tumor suppressor genes

  Induce a recessive phenotype → cell survival and proliferation
• HER2


  Human epidermal growth factor receptor 2
• HER2+ breast cancer


  Breast cancer cell is overexpressing HER2; provides mechanism for increase in cell division
• Treatment for HER2+ breast cancer

  Often treated with herceptin: monoclonal antibody that binds to extracellular domain of EGFR
• Tyrosine kinase inhibitor (TKI)


  Small molecule that binds to intracellular domain of EGF and inhibits kinase activity
• Targeted therapy (aka personalized medicine)

  Drugs that target specific genes and proteins that contribute to cancer growth and survival
• Steps in targeted therapy

  1. Diagnose type of cancer

  2. Perform genetic testing on tumor cells to identify target

  3. Provide patient with a drug that targets that gene
• Ras converted into an oncogene


  • The G/T mutation in 12th codon prevents Ras from hydrolyzing bound GTP
  • Loss of GTPase activity means that once Ras is activated its always on (gain of function)
• If Ras is always on

  Different pathways are constantly activated which can cause cancer
• Rb gene


  Tumor suppressor gene that regulates cell division by inhibiting the progression of cell cycle
• Cyclins and Cdks


  Proteins that regulate cell cycle
• Knudson's two-hit hypothesis


  Two different genetic alterations (two hits) at one tumor suppressor gene are required for tumor initiation
• Presence of germline mutation at tumor suppressor gene


  Increases probability both copies will be inactivated
• Differences between hereditary and non-hereditary (sporadic) cancers

  • Hereditary cancer caused by one germline mutation and one somatic mutation at tumor suppressor gene (associated with cancer syndrome)
  • Non-hereditary (sporadic) cancers require two somatic mutations
• Cancer syndrome


  Germline mutation at tumor suppressor gene causes early onset of cancer and predisposes individuals to different types of cancer
• Differences between familial and sporadic retinoblastoma

  • Hereditary retinoblastoma: individual has germline mutation at Rb then acquires second mutation after birth
  • Non-hereditary: two somatic mutations are acquired after birth
• p53 and Bak


  Tumor suppressor genes that help prevent cancer by regulating cell cycle progression and promoting apoptosis in response to DNA damage or other abnormalities
• BclxL


  Proto-oncogene that promotes cell survival and can contribute to cancer development when dysregulated
• Five steps of metastasis

  1. Invasion: cancer cell leaves primary tumor

  2. Intravasation: cancer cell enters bloodstream

  3. Transport: cancer cell travels in bloodstream

  4. Extravasation: cancer cell leaves bloodstream

  5. Colonization: cancer cell makes secondary tumor
• Cadherin genes


  Their mutations contribute to metastasis by allowing cells to dissociate from the primary tumor, invade surrounding tissues, and migrate to distant sites