A 55-year-old woman has breast carcinoma with HER2 (ERBB2) gene amplification confirmed by FISH. HER2 overexpression drives tumor growth through which mechanism?

• A Nuclear estrogen receptor activation independently of ligand
• B Overexpression of cyclin D1 directly causing G1/S cell cycle progression
• C Direct inhibition of p53-mediated apoptosis in tumor cells
• D Constitutive activation of PI3K/Akt and MAPK signaling through homodimerization ✓

Explanation

HER2 (ErbB2) is a receptor tyrosine kinase with no known direct ligand that constitutively homodimerizes or heterodimerizes with other ErbB family members when overexpressed. This activates PI3K/Akt (pro-survival) and RAS/MAPK (proliferative) downstream pathways without requiring ligand engagement. Trastuzumab targets the HER2 extracellular domain to inhibit this signaling. HER2 overexpression is independent of ER status.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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