Mechanisms / Pathophysiology of Breast Cancer

  • The exact mechanism by which breast cancer is initiated is unknown:
    • However, much effort has been made to molecularly characterize breast cancer and delineate its formation and progression
  • At the cell of origin level:
    • The clonal evolution model:
      • In which mutations accumulate
      • Epigenetic changes in tumor cells occur
      • The ‘fittest’ cells survive
    • The cancer stem cell model:
      • In which only the precursor cancer cells:
        • Initiate and sustain progression
    • The clonal evolution model and the cancer stem cell model:
      • Are both implicated, and further complicated by the fact that cancer stem cells may also evolve in a clonal fashion
  • At the morphological level:
    • There is a continuum of lesions and genetic modifications from normal glands to cancer
  • At the molecular level:
    • There is evidence showing that breast cancer evolves along two divergent molecular pathways of progression:
      • Mainly related to ER expression, and tumor grade and proliferation:
        • Described in the intrinsic classification
      • Furthermore, the identification of breast cancer susceptibility genes:
        • Has shed the light on some aspects of the pathogenesis of both sporadic and inherited breast cancer
      • The first pathway:
        • The low-grade-like pathway — is characterized by gain of 1q, loss 16q, infrequent amplification of 17q12 and a gene expression signature (GES) with a majority of genes associated with the ER phenotype, diploid or near diploid karyotypes and low tumour grade. The luminal A group and to some extent the luminal B group fall into this pathway. The second pathway — the high-grade-like pathway — is charac- terized by loss of 13q, gain of chromosomal region 11q13, amplification of 17q12 (containing ERBB2, encoding HER2) and an expression signature of genes involved in the cell cycle and cellular proliferation61. Tumours composed of intermediate to high grade, including HER2-positive tumours and TNBC, fall into this pathway

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