Abstract
The overexpression of human epidermal growth factor receptor 2 (HER2) is associated with increased breast cancer recurrence and worse prognosis. Effective treatments such as trastuzumab and lapatinib for patients with HER2 overexpression target the blockade of HER2 signaling activities but are often limited by the emergence of acquired drug resistance. This study applied Raman spectroscopy to differentially identify the amplification status of HER2 in cells and to characterize the biochemical composition of lapatinib resistant and sensitive HER2+ breast cancer cells in response to the drug. Raman spectra from BT474 (HER2+ breast cancer cell), MCF-10A (HER2- control), and HER2+ MCF-10A (HER2+ control) were analyzed using lasso and elastic-net regularized generalized linear models (glmnet) for multivariate statistical analysis and were discriminated to groups of different HER2 expression status with an overall 99% sensitivity and specificity. Enhanced lipid content and decreased proteome were observed in HER2+ cells. With lapatinib treatment, lapatinib-resistant breast cancer cells demonstrated sustained lipogenesis compared with the sensitive cells.
Highlights
The human epidermal growth factor receptor 2 (HER2) protein and the HER2/neu oncogene make an important contribution to the regulation of cell proliferation and survival
To further investigate the biochemical differences between the cell lines, spectra were subtracted to reveal the difference between HER2+ BT474 cancer cells and controls
This study reports a sensitive identification of HER2 amplified cell lines, which proves the potential of Raman spectroscopy (RS) in determining HER2 status in breast cancer cells
Summary
The human epidermal growth factor receptor 2 (HER2) protein and the HER2/neu oncogene make an important contribution to the regulation of cell proliferation and survival. Amplification of HER2/neu gene occurs in approximately 20% to 25% of human breast cancers[1,2,3] and is associated with a more aggressive disease course and poor prognosis.[3,4] Besides increased disease recurrence and short survival, HER2 amplification status is predictive for resistance to certain endocrine and chemotherapeutic agents.[5,6] Patients with HER2+ breast cancer require specific treatments targeting blockade of HER2 activity with monoclonal antibodies [e.g., trastuzumab (Herceptin)] and small molecule tyrosine kinase inhibitors (e.g., lapatinib). The IHC analysis stains HER2 protein on the cytoplasmic membrane through specific antibody and scores protein expression status based on the color of the stains. This qualitative test is subjected to interlaboratory variation and is relatively less sensitive than FISH. The main disadvantages of this method include the expensive cost and time-consuming analysis that
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