Oncogenes

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Oncogenes

• Brief Outline of Major Teaching Points
• Introduction
• Genetics of avian tumor, e.g., Rous sarcoma virus
• Other facts about avian tumor viruses
• virus src vs. cellular src genes (v-src vs.
  c-src)
• the src gene product
• avian leucosis and other avian tumor viruses,
  e.g., c-myc
• Viral and cellular oncogenes, e.g., v-src

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Breast Cancer and Oncogene

• One in 9 women will develop breast cancer in her
  lifetime.
• The ACS estimates about 200,000 new cases this
  year and over 50,000 women will die from the
  disease.
• Aside from risk factors such as family history,
  alcohol consumption, dietary fat and cigarette
  smoking, there are several genetic alterations
  observed in breast malignancies.
• These include amplification of c-Myc and HER2/neu
  and loss of heterozygosity (LOH) in several
  locations that reflect recessive mutations
  characteristic of tumor suppressor genes, such as
  17p or p53 (70 of breast tumors have deletions
  here).

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• Two important Cancer Suseptibility Genes are
  related to breast cancer
• BRCA-1 If it is inherited in a mutated form,
  women are highly susceptible to breast and
  ovarian cancer (80 of families).
• BRCA-2 Since both copies of the gene must be
  damaged or lost in breast tumors of women who
  inherit the mutant gene, it suggests that the
  gene normally functions as a Tumor Suppressor
  Gene.

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Prostate cancer and oncogenes

• Prostate cancer (PCa) is a leading cause of
  cancer death and cancer-related mortality in men
  in the western world.
• There is no cure for advanced metastatic prostate
  cancer (9-12 months survival rate)
• No oncogene has been linked conclusively with the
  initiation of early progression of PCa.
• In addition to the classic oncogenes, a number of
  biological markers including the proliferation
  markers, neuroendocrine markers, cytokeratins,
  stromal factors and even blood group antigens
  have been implicated in PCa.

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• In addition to androgen, a variety of growth
  factors, small active peptides, and other trophic
  agents have also been implicated in prostate
  carcinogenesis and metastasis to bone.
• Although not among the recognised oncogenes, if
  the protein is over-active and contributes to
  prostate carcinogenesis, or metastasis, it could
  be termed a prostate-specific 'oncogene'.

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Oncogenes with potential involvement in PCa

• Of the oncogenes, the RAS gene family (Harvey
  (H), Kirsten (K) and neuroblastoma (N) RAS), have
  been most widely studied in PC.
• The diagnostic assessment of RAS proteins in PCa
  has not yielded clinically useful prognostic
  information.
• RAS mutations were relatively uncommon in PCa in
  the United States with no prognostic utility.
• Interestingly, there appear to be racial
  variations in RAS mutation rates, as well as
  differences between clinically-detected and
  autopsy PCa cases.
• In cases from Japan, in both incidentally
  discovered and advanced PC, about 25 appear to
  harbor RAS mutations. The clinical implications
  of these results are still unclear.

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• The MYC family of oncogenes, in particular c-MYC,
  has also received attention in PCa.
• c-Myc, a transcription factor involved in
  differentiation and the level of C-MYC mRNA is
  higher in proliferating cells.
• c-MYC mRNA is elevated in PCa, compared to BPH or
  normal prostate tissue and in high-grade tumors.
• Approximately 70 of PCa and BPH samples express
  c-MYC protein. Given this c-MYC expression in
  BPH, it is not surprising that there was no
  correlation of this with survival.

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• c-ERB-B2 another oncogene studied in PCa
• Its clinical utility as a tumour marker or
  therapeutic target remains unclear.
• Unlike in breast cancer, c-ERB-B2 is not
  frequently amplified in PCa.
• Increased C-ERB-B2 copy number appears to be rare
  in clinically localised PCa, but C-ERB-B2
  overexpression has been reported in up to 60 of
  patients with hormone-refractory PCa. This
  correlated with a decrease in survival

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Summary

• Proto-oncogenes participate in normal cell
  proliferation, encoding a variety of proteins
  that act as growth factors/receptors,
  transcription factors, modifiers of signaling
  pathways.
• Any alterations to these critical processes can
  cause aberrant growth and contribute to
  neoplastic transformation.
• Protooncogenes can be activated by insertional
  mutagenesis, amplification,point mutation, and
  translocation.
• These alterations could convert a protooncogene
  to an oncogene and due to the dominant expression
  pattern, the presence of an oncogene is
  tumorigenic

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Animal Model of Bone Metastases in Breast and
Prostate Cancer
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In vivo bioluminescent imaging of light emitted
from luciferase in human PC-3M-Luc prostate
cancer cells in nude mice
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Frequency of Bone metastases in 14 rapid autopsy
patients
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Multi-step process of breast or prostate cancer
metastases
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EGF/Heregulin signaling
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IGF-I/Akt-signaling
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Metastatic prostate and breast cancer in the dog
femur
Osteoblastic Prostate Cancer
Osteolytic Breast Cancer