Dr. Jamil Momand | Towards an Understanding of Resistance to Herceptin in Breast Cancer

October 1st, 2025

Seminar at 9:00 am - Q&A at 10:00 am

Title: Towards an understanding of resistance to Herceptin in breast cancer 

Abstract:

Trastuzumab (Herceptin) is a monoclonal antibody drug used in combination with chemotherapy for early-stage HER2+ breast cancer that has spread to the lymph nodes or is node-negative with certain high-risk features. It is also used in combination with chemotherapy to treat metastatic HER2+. We set out to uncover transcriptome and chromatin landscape changes that occur in HER2 + breast cancer (BC) cells upon acquiring resistance to trastuzumab. RNA-seq analysis was applied to two independently-derived BC cell lines with acquired resistance to trastuzumab (SKBr3.HerR and BT-474HerR) and their parental drug-sensitive cell lines (SKBr3 and BT-474). Chromatin landscape analysis indicated that the most significant accessibility increase in resistant cells occurs in PPP1R1B within a segment spanning introns 1b through intron 3. Footprint analysis of this segment revealed that FoxJ3 (within intron 2) and Pou5A1/Sox2 (within inton 3) transcription factor motifs are protected in resistant cells. Overall, 344 shared genes were upregulated in both resistant cell lines relative to their parental counterparts and 453 shared genes were downregulated in both resistant cell lines relative to their parental counterparts. In resistant cells, genes associated with autophagy and mitochondria organization are upregulated and genes associated with ribosome assembly and cell cycle are downregulated relative to parental cells. The five top upregulated genes in drug-resistant breast cancer cells are APOD, AZGP1, ETV5, ALPP, and PPP1R1B. This is the first report of increased chromatin accessibility within PPP1R1B associated with its t-Darpp transcript increase, and points to a possible mechanism for its activation in trastuzumab-resistant cells. t-Darpp protein is an N-terminal-truncated version of Darpp-32, a phosphatase inhibitor. t-Darpp binds calcium and is a disordered protein. The mechanism by which it mediates traustuzamab resistance is being investigated.
 

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Dr. Jamil Momand

Professor of Biochemistry, Bioinformatics Minor advisor
California State University Los Angeles

JMomand@calstatela.edu | Personal page

Host: Mary Sehl

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