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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology

3747 - HER2-positive breast cancer resistance to trastuzumab is associated with metabolic switch.

Date

21 Oct 2018

Session

Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology

Presenters

Roman Dubianski

Citation

Annals of Oncology (2018) 29 (suppl_8): viii1-viii13. 10.1093/annonc/mdy268

Authors

R. Dubianski1, E. Sarnowska2, M. Leszczynski2, S. Kubala3, W. Olszewski4, N. Rusetska2, A.I. Jagiello-Gruszfeld1, R. Konopinski2, T.J. Sarnowski3, J.A. Siedlecki2, Z.I. Nowecki1

Author affiliations

  • 1 Department Of Breast Cancer And Reconstructive Surgery, The Maria Skłodowska Curie Memorial Cancer Centre and Institute of Oncology (MCMCC), 02-781 - Warsaw/PL
  • 2 Department Of Molecular And Translational Oncology, The Maria Skłodowska Curie Memorial Cancer Centre and Institute of Oncology, 02-781 - Warsaw/PL
  • 3 Department Of Protein Biosynthesis, Institute of Biochemistry and Biophysics PAS, 02-106 - Warszawa/PL
  • 4 Department Of Pathology And Laboratory Medicine, The Maria Sklodowska-Curie Memorial Institute and Oncology Centre, 02-781 - Warsaw/PL
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Resources

Abstract 3747

Background

Overexpression of the HER2 (ErbB2 or HER2/neu) receptor occurs in 20-25% of breast cancer patients population and is related to more aggressive disease. Implementation of trastuzumab to the treatment of HER2-positive breast cancer improved the results of the treatment in this subgroup of patients. However, the resistance to trastuzumab occurs in some patients. The presence of the nuclear localization of HER2 was also noticed. The aim of this work was to verify the molecular basis of resistance to transtuzumab and correlation between the resistance and the nuclear localization of HER2 protein.

Methods

Among more than 650 patients treated with trastuzumab in MSCMCC 50 patients with resistance to trastuzumab, and 50 well responding to the treatment were chosen. The percentage of the cells with HER2 localized in the nucleus were counted. Additionally, the transcriptomic analysis of HER2 positive breast cancer cell line resistant to trastuzumab was performed. The HER2 ChIP seq and Co-IP from SK-BR3 cell nuclei followed by mass spectrometry analysis were obtained.

Results

In breast cancer with HER2 overexpression nuclear staining was present in immunochemistry. The comparative transcriptomic reanalysis of GEO datasets performed on trastuzumab resistant cell lines and sensitive cell lines revealed that in trastuzumab resistant cell lines the reprogramming of cell metabolism takes place. The most common disturbances were detected in the expression of genes involved in the lipids metabolism, glycolysis and vitamin A metabolism. Moreover, among 308 genes upregulated in trastuzumab resistant breast cancer cells the 216 genes were directly bound/regulated by BRG1 ATPase-the core subunit of SWI/SNF chromatin remodeling complex which is known regulator of metabolism related genes. Among 151 downregulated genes 67 were directly targeted by BRG1. Similarly, the another SWI/SNF ATPase (BRM) – directly targeted 151 of 308 upregulated and 32 of 151 downregulated genes. These results strongly suggested the direct regulation or interdependence of HER2 and SWI/SNF complex.

Conclusions

In HER2 cancer cells resistant to transtuzumab treatment the strong metabolic switch is observed. Moreover, the SWI/SNF complex and nuclear HER2 can be involved in this process.

Clinical trial identification

Legal entity responsible for the study

Maria Sklodowska - Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.

Funding

Maria Sklodowska - Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.

Editorial Acknowledgement

Disclosure

All authors have declared no conflicts of interest.

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