Fig. 19.27 ). Other mutated genes associated with familial breast cancer include TP53 (the so-called “guardian of the genome”, Chapter 6) and PTEN (an important negative regulator of the pro-growth PI3K-AKT pathway), already mentioned earlier as a risk factor for endometrial carcinoma as part of Cowden syndrome.
As might be expected, the pathways in which familial breast cancer genes function also are often disturbed in sporadic breast cancers. Somatic mutations in BRCA1 and BRCA2 are rare in sporadic cancers, but BRCA1 is inactivated by methylation in up to 50% of triple-negative cancers. Somatic mutations in TP53 are common in breast cancer, particularly triple-negative and HER2-positive tumors (
Table 19.7 ), whereas mutations that activate PI3KAKT signaling are frequently found in sporadic ER-positive and HER2-positive breast cancers (
Fig. 19.27
A common clinically important driver mutation in breast cancer is amplification of the HER2 gene. HER2 is a receptor tyrosine kinase that promotes cell proliferation and opposes apoptosis by stimulating the RASand PI3K-AKT signaling pathways. Cancers that overexpress HER2 are pathogenically distinct and highly proliferative. In the past they had a poor prognosis; however, the availability of therapeutic agents that specifically target HER2 has markedly improved the prognosis for patients with HER2-amplified tumors.
http://ebooksmedicine.net (50-65% of cancers) 1q 16q PIK3CA gain loss mutations “Luminal”
HER2 Positive (20% of cancers) Normal breast Germline HER2 “HER2 TP53 mutations amplification enriched”
Fig.19.27Majorpathwaysofbreastcancerdevelopment.Themostcommonpathway(yellow arrow) leadstoER-positivecancers.Morphologicallyrecognizedprecursorlesionsincludeflatepithelialatypia,ADH,andDCIS,allofwhichsharecertaingenomiceventswithinvasiveER-positivecarcinomas,suchgainsofchromosome1,lossesofchromosome16,andmutationsofPIK3CA (thegeneencodingPI3K).Bygeneexpressionprofiling,thesecancersareclassifiedas“luminal.”ThisisthetypeofcancerthatarisesmostcommonlyinindividualswithgermlineBRCA2 mutations.LesscommonarecancersthatoverexpressHER2becauseofgeneamplification(green arrow).ThesecancersmaybepositiveornegativeforERandareusuallyassociatedwithgermlineTP53 mutations.Apossibleprecursorlesionisatypicalapocrineadenosis,whichsharesfeatureswithapocrineDCIS.TheleastcommonbutmolecularlymostdistinctivetypeofbreastcancerisnegativeforERandHER2(“triplenegative”;blue arrow).ThesecancershavelossofBRCA1 andTP53 functionandaregenomicallyunstable.Themajorityoftriple-negativecancersareclassifiedas“basal-like”bygeneexpressionprofiling.
Hormonal Influences. Estrogens stimulate the production of growth factors, such as transforming growth factor-α, platelet-derived growth factor, fibroblast growth factor, and others, which may promote tumor development through paracrine and autocrine mechanisms. In addition, ER regulates dozens of other genes in an estrogen-dependent fashion, some of which are important for tumor development or growth. Hormonal influences likely drive proliferation during the development of cancers from precursor lesions (which typically strongly express ER) to fully malignant and even metastatic carcinomas. The clearest measure of the importance of estrogen is found in the therapeutic benefits of estrogen antagonists, which reduce the development of ER-positive cancers in women at high risk and are mainstays in the treatment of established ER-positive tumors.