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- Predictive molecular markers for breast cancer therapy commonly used in clinics? IHC: -Receptor status & proliferation status is determined -ER and PR -HER2 -Ki67 (nuclear protein with elevated levels in cycling cells (S-phase, mitosis and G2) Gene profiling: -Luminal A (ER+, good prognosis) -Luminal B (ER+, prognosis not as good as luminal A) -normal breast-like /gene signature similar to normal breast) -HER2 amplified (HER positive) -basal hormone receptor and HER2 negative (triple negative)
- Explain the differences between SERMs and aromatase inhibitors to block estrogen signalling? SERM (selective estrogen receptor modifiers): -e.g. tamoxifen -structure of SERM is planar like estrogen; hydrophobic -bind to the ligand-binding pocket of the ER -4-OH tamoxifen induces different helix 12 conformation change compared to the normal agonists (estrogen) → due to bigger size of tamoxifen -recruitment of co-activators inhibited in the case of 4-OH tamoxifen binding -have a tissue dependent activity → good, tamoxifen cannot block beneficial estrogen activity in bones, but as side effects, it can induce strokes Aromatases inhibitors: -Typ I (e.g. exemestane, steroid-like structure) -Typ II (e.g. anastrozole, letrozole) -inhibitors of aromatase (key enzyme for estradiol synthesis out of testosterone; present in ovaries, adipose tissue and testis) -effective in the absence of ovary function -cannot significantly reduce estrogen levels in premenopausal women with functional HPO (hypothalamic–pituitary–gonadal) axis. Reason: inhibitor is not strong enough to override the feedback loop of estrogen production
- Paracrine mediators of progesterone action in the mammary gland? -RANKL (Activator of NF-kappaB Ligand) mediates the paracrine action of progesterone leading to: → cell division in ER- and PR- cells → Signal amplification and coordination -WNT4 promotes “stemness” of mammary epithelial stem cells and proliferation of basal cells
- Modes of resistance to HER2/EGFR targeted therapy? Resistance to therapy: -mutation of receptor -constitutive signaling of receptor down-stream signaling events -upregulation of alternative signaling pathways which bypass HER2 and EGFR
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