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.
Resources from the same session
1159 - Molecular characterization and search for founding effects in Canarian families with Hereditary Breast and Ovarian Cancer Syndrome
Presenter: Elisenda Llabres Valenti
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
Resources:
Abstract
3725 - Effect of the polymorphism rs2066844 of the NOD2 gene on colon cancer incidence in a high cardiovascular risk population. Modulation by gender
Presenter: Judith Begona Ramirez Sabio
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
Resources:
Abstract
3708 - Effect of the polymorphisms rs1476413, rs1801131, rs4846052 and rs6541003 of the MTHFR gene on prostate cancer in a high cardiovascular risk population
Presenter: Judith Begona Ramirez Sabio
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
Resources:
Abstract
5057 - Association of a genetic variant in cyclin-dependent kinase Inhibitor 2A gene with the increased risk of breast cancer
Presenter: Soodabeh Shahid Sales
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
Resources:
Abstract
5970 - Investigating the role of HAT protein TIP60 in regulating functional dynamics of nuclear receptor PXR
Presenter: KARISHMA BAKSHI
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
Resources:
Abstract
1360 - The role of downregulated SIRT3 expression in patients with hepatocellular carcinoma
Presenter: Hanhee Jo
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
Resources:
Abstract
1634 - Prediction and Intervention of Colorectal Cancer Risk with Artificial Intelligent System
Presenter: Yang Ge
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
Resources:
Abstract
4921 - Measuring the Efficiency of Cancer Care in Europe
Presenter: Rikard Althin
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
Resources:
Abstract
1235 - Circulating cell-free DNA isolated from plasma of mesenteric veins predicts prognosis in stage II colorectal cancer patients
Presenter: Chih-Yung Yang
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
Resources:
Abstract
5169 - _lonality of uterine carcinosarcoma as a factor of clinical prognosis.
Presenter: Natalia Levitskaya
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
Resources:
Abstract