8-2-11-tumour-development

Tumour development

Cancer and uncontrolled cell division

• Cancer arises from uncontrolled mitosis due to mutations in genes regulating the cell cycle

• Cancerous cells divide uncontrollably, forming a tumour

• Mutations in genes that regulate cell division can lead to cancer; these genes may become oncogenes

• Mutations are common events and don’t lead to cancer most of the time

  • Most mutations either result in early cell death or in the cell being destroyed by the body’s immune system

  • As most cells can be easily replaced, these events usually have no harmful effect on the body

• Harmful mutations that escape these mechanisms can be passed to all descendant cells

• Carcinogens (e.g. UV, tobacco tar, X-rays) increase mutation risk

Tumour suppressor genes

• Tumour suppressor genes are normal genes which encode proteins that:

  • Repair DNA

  • Slow the cell cycle at checkpoints

  • Signal apoptosis if damage is irreparable

• Mutations or epigenetic silencing of tumour suppressor genes can lead to tumour formation

• BRCA-1 is a tumour suppressor gene mainly expressed in breast tissue

  • The BRCA-1 protein repairs damaged DNA or triggers apoptosis if repair fails

  • Reduced BRCA-1 expression leads to breast cancer development

Oncogenes

• Proto-oncogenes code for proteins that stimulate cell growth and differentiation

• Mutation (due to carcinogens) can convert proto-oncogenes into oncogenes

  • Causes constant activation of proteins that stimulate cell growth and division

    • This speeds up the cell cycle

  • If proteins that induce apoptosis are also affected, tumours can form

• Oncogene activation can occur via:

  • inversion or translocation mutations on a proto-oncogene leading to:

    • increased gene expression

    • protein production cannot be switched off

Abnormal methylation

• Abnormal methylation of DNA affects gene expression:

  • Increased methylation of tumour suppressor genes silences them as transcription factors are unable to bind

    • tumour suppressor proteins are therefore not synthesized and tumour formation occurs

    • RNA interference by siRNAs targeting tumour suppressor genes for breakdown can also lead to tumour development for the same reason

  • Reduced methylation of proto-oncogenes increases expression as the gene becomes accessible

    • transcription factors then bind and protein synthesis is activated

    • the gene behaves like an oncogene, even without a mutation

Oestrogen-dependent breast tumours

• Oestrogen is a steroid hormone that upregulates transcription of certain genes through the stimulation of the ERα oestrogen receptor

  • High concentrations of oestrogen can lead to the development of breast cancer

  • High concentrations can be a result of over-expression of the oestrogen gene or from supplementary oestrogen taken in medication

• ~70% of breast tumours are oestrogen receptor-positive

  • Oestrogen enters cells, binds to oestrogen receptors in the nucleus which activates transcription

  • This stimulates the expression of cell cycle genes that lead to growth and replication

• The drug tamoxifen is a competitive inhibitor of oestrogen:

  • It binds ERα receptor and prevents gene activation

  • This inhibits tumour growth as the oestrogen receptor cannot bind to the promoter