i-Human Breast Cancer 2023 with verified questions and answers

Risk factors for BC Advancing age (70 highest risk), gender, FHx, BRCA, early menarche (before 12, longer estrogen expsosure), later first pregnancy (after 35, uninterrupted estrogen over long time), late menopause (after 55), hormone replacement therapy, radiation exposure, other personal or FHx of malignancy, previous abnormal breast biopsy, previous breast biopsy (atypical ductal hyperplasia), alcohol What questions to ask in HPI related to BC? -Nipple discharge: hormones, breast feeding, cancer esp. if bloody, if bilateral more indicative of benign mass -Skin dimpling: cancer usually has invasive nature so skin not smooth -Fixed (not moveable): malignant characteristics of anchoring into tissue What to do on PE in BC? Breast exam, lymph nodes (infection, malignancy travels in lymph), listen to lungs (no sign of spreading to lungs), check abdomen (make sure liver/spleen not enlarged), tumor fever, inversion of nipple, irregular border, large size, nipple discharge, fixed/firm, check both sides DDx BC Cyst, Hematoma (due to trauma, usually tender), Soft tissue infection/tis, genetic disorder, malignant mass, benign mass, Fibrosis/scarring Construct a concept map that represents what you observe in a rapidly dividing cell line within a very aggressive malignant tumor in a breast cancer patient. Include G1, M, S, G2 DNA Synthesis (S) -- G2 -- Mitosis -- G1 Going from DNA synthesis to G2, Retinobalstoma protein is ______ a. Phosphorylated b. Hypo-phosphorylated a. Phosphorylated Going from Mitosis to G1, Retinoblastoma protein is ______ a. Phosphorylated b. Hypo-phosphorylated b. Hypo-phosphorylated Mechanism by which EGF generates a biological response at target cell -EGF -- EGFR -- 2nd messenger -- altered enzyme activity -- biological response **2nd messenger can alternatively cause altered gene expression which can lead to a biological response Betty Burns is treated with monoclonal antibodies that bind to the EGF receptor. The receptor is a tyrosine kinase and binding of EGF to the receptor initiates a second messenger signaling cascade which leads to increased cell proliferation, increased glycolysis, and increased protein synthesis. It is ALSO possible to treat some breast cancers with drugs that act by competitive inhibition at the EGF receptor. If Betty's body were to increase its level of production of EGF in response to a drug which is competitive for EGF, this would lead to resistance to treatment because: a. The amount of EGF which the receptor transports into the cell is increased b. The EGF binds to a site which not the same as the inhibitor binding site. Thus the conformation of the inhibitor binding site would change in response to extra EGF such that it would no longer bind the inhibitor. c. More EGF increases the odds that EGF is bound to the receptor and decreases the odds that the inhibitor is bound to the receptor. d. More EGF shifts the apparent Kd of the receptor to the left. (The Kd is similar to the Km in enzyme kinetics. It is the concentration necessary to occupy half of the receptors) e. More EGF increases the apparent Bmax. (The Bmax is similar to Vmax in enzyme kinetics. It is the maximal amount of a substrate which can bind to the receptors) c. More EGF increases the odds that EGF is bound to the receptor and decreases the odds that the inhibitor is bound to the receptor. ** NOTE: Drugs which alter Bmax of enzymes are non-competitive. Answer d is not correct because increasing EGF increases hormone binding to the receptor without shifting the apparent Kd. Many patients develop resistance to erlotinib within months of beginning treatment. This drug is a competitive EGFR receptor inhibitor. Which of the following is a reason for this development? a. A mutation of the EGFR exist which increases the receptor's ATP binding affinity b. Mutation of EGFR which increases the receptor's affinity for Gs c. Down-regulation of the enzymes which metabolize the drug d. Changes in the cell membrane composition which decrease the membrane permeability of the drug a. A mutation of the EGFR exist which increases the receptor's ATP binding affinity **NOTE: The EGFR receptor is a tyrosine kinase. Binding of EGF to the receptor causes initiation of the MAPK/ERK signaling pathway through phosphorylation of target proteins. Tyrosine kinase needs to bind and use ATP in order for phosphorylation to take place. Increasing the ATP binding affinity of the receptor makes it more effective at initiating this cascade partially offsetting the effects of the inhibitor. Active Mammary has _____ ducts and nuclei, inactive mammary is a mass mostly of _______interspersed with ______ very little ______ tissue in inactive mammary Active Mammary has many ducts and nuclei, inactive mammary is a mass mostly of connective tissue interspersed with white stuff (adipose tissue), very little glandular tissue in inactive mammary Atypical proliferating cells are integrated into the ____ cell layer of the duct and have compromised ______. -Basal layer -Basal lamina Factors that contribute to invasive behavior of cancer -Integrin signaling → Down regulates E-cadherin → disrupts cell-cell adhesion allowing augmented cell motility through BM. Also upregulates MMP → results in degradation of matrix components (allows them to move through matrix and give cells increased motility through BM -Laminin → Abnormal expression promotes migration (important for adhesion of cells, promotes migration of cancerous tissue through cells. Mostly allows cells to get out of tissue and move to distal sites. BRCA1/2 and NBS Participate in the repair of DNA. If missing don't repair DNA and lead to cancer. Mutations are present in 5-10% of breast cancer. ATM Detects DNA damage and controls DNA repair Epithelial to Mesenchymal Transition TJ dissociation and loss of microvilli → adherent-junction and desmosome dissociation and loss of apical-basal polarity → aSMA expression cytoskeleton reorganization, front-back polarity migration → MMP up-regulation, basement membrane degradation, and invasion. Moves from non motile → motile (ability to break through BM) Which are Epithelial Markers? E-cadherin, Claudins, Occludins, ZO-1, Desmoplakin, Cytokeratins Which are Mesenchymal Markers? N-cadherin, fibronectin, Collagen I/III, Snail, aSMA, Vimentin VEGF In Tumor Angiogenesis Tumor secretes VEGF → VEGF increases endothelial protease expression → Endothelial cell migration and proliferation promoted by VEGF → Microvascular networking promoted by VEGF Prevalence of Breast Cancer (types most to least common) Luminal A (40%) Luminal B (20%) Triple Negative (15-205) HER 2 (10-15%) Severity of breast cancer types (most to least severe) Triple Negative HER2 Luminal B Luminal A Gene and Protein testing for BC IHC (protein), FISH (DNA or mRNA), PCR, gene microarrays, lymph node and tissue biopsies ER and PR hormone inhibitors Cytoplasmic/nuclear receptor. 2/3 breast cancer patients are ER and/or PR +. Estrogen stimulates cell proliferation. Inhibitors of ER-estrogen complex may interfere with ER/PR tumors (oophorectomy, tamoxifen, aromatase inhibitors, SERM, SERD) HER Family -HER2 is an extracellular receptor, dimerizes for activation, does not bind ligand -Amplified in ~20% of breast cancers -Correlates with size, node status, recurrence, stage at presentation -Up to 20 extra gene copies of HER2 cause up to 100x protein concentration HER2 -HER2 does not bind a ligand but dimerizes with other HER receptors for activation. HER1, 3, 4 bind EGF ligand (which causes dimerization) -HER 1, 2, 4 have TK in cytoplasmic tail -Dimerization activates TK domain Which HER receptors bind ligands? HER 1, 3, 4 Which HER receptor does not have a cytoplasmic tail? HER3 Are heterodimers or homodimers of HER family more active? Heterodimers Which combination of HER receptors is most active and why? -HER2/HER3 -Because of slow release of ligand and slow turnover of receptor Trastuzumab -Herceptin -Monoclonal antibody binds HER2, blocks dimerization, decrease HER2 activity, targets cells for immune destruction Pertuzumab Binds to different extracellular domain of HER2. Can be used in combination with Traztuzumab to enhance effects Trastuzumab-DM1 New antibody conjugate with potent fungal toxen. Inhibits HER2 activity and toxin kills cell.