What are major pathways of development of breast cancer?

➢ The most common pathway (yellow arrow) leads to ERpositive cancers. ➢ Morphologically recognized precursor lesions include flat epithelial atypia, ADH, and DCIS, all of which share certain genomic events with invasive ER-positive carcinomas, such gains of chromosome 1, losses of chromosome 16, and mutations of PIK3CA (the gene encoding PI3K). ➢ By gene expression profiling, these cancers are classified as "luminal.” ➢ This is the type of cancer that arises most commonly in individuals with germline BRCA2 mutations ➢ Less common are cancers that overexpress HER2 because of gene amplification (green arrow). ➢ These cancers may be positive or negative for ER and are usually associated with germline TP53 mutations. ➢ A possible precursor lesion is atypical apocrine adenosis, which shares features with apocrine DCIS. ➢ The least common but molecularly most distinctive type of breast cancer is negative for ER and HER2 (“triple negative”; blue arrow). These cancers have loss of BRCA1 and TP53 function and are genomically unstable. ➢ The majority of triple-negative cancers are classified as “basallike” by gene expression profiling.