A 55-year-old woman with breast carcinoma has biopsy showing HER2/neu gene amplification by FISH (HER2:CEP17 ratio >2.0). HER2 overexpression drives tumour proliferation via which primary signalling mechanism?

• A HER2 functions as a serine/threonine kinase that phosphorylates SMAD proteins activating TGF-β signalling
• B HER2 overexpression upregulates cyclin D1 directly by nuclear translocation
• C HER2 amplification causes transcriptional activation of ER target genes
• D Constitutive homo- or heterodimerisation of HER2 activates PI3K/AKT/mTOR and RAS/MAPK pathways without ligand binding ✓

Explanation

HER2 (ErbB2/neu) is an orphan receptor tyrosine kinase with no known direct ligand; it preferentially acts as a dimerisation partner for other HER family members (HER1, HER3, HER4). When HER2 is overexpressed (gene amplification in 15–20% of breast cancers), spontaneous homo- and heterodimerisation occurs constitutively, triggering autophosphorylation and downstream activation of PI3K/AKT/mTOR (survival/proliferation) and RAS/RAF/MEK/ERK (proliferation) pathways. Trastuzumab (Herceptin) binds domain IV of HER2 extracellular domain, blocking these survival signals.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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