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

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. 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. Disclosure: All authors have declared no conflicts of interest.