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24 April 2018
Treatment resistance is a main cause of adverse disease outcome in breast cancer patients. Therefore, this study aimed to identify common features of tamoxifen- and radioresistance in breast cancer cells in vitro and investigate relevant pathways in patient cohorts to establish the relevance of the identified pathways.
Both tamoxifen- and radioresistant breast cancer cells had increased expression levels of genes involved in type I interferon signaling, compared to non-resistant cells. IFN-stimulated genes (ISGs) were induced in a dose-dependent and time-dependent manner after tamoxifen treatment and irradiation. Tamoxifen treatment also led to ssDNA presence in the cytoplasm, a phenomenon that has already been described for irradiation and is known to induce expression of ISGs.
Several breast cancer patient cohorts were analyzed to investigate the relation of ISG expression with treatment sensitivity. In one cohort, high expression levels of ISGs were found in the primary tumor in around half of the patients. This was associated with a tumor infiltrating lymphocyte expression signature, while the ISGs were also expressed by the tumor cells themselves. Importantly, the expression of ISGs correlated to outcome in breast cancer patients treated with adjuvant tamoxifen or radiotherapy, but not in systemically untreated patients or chemotherapy-treated patients.
These data indicate that expression of ISGs by tumor cells is involved in acquired, treatment-induced resistance to tamoxifen and radiotherapy, and might play a role in intrinsic resistance via interaction with tumor infiltrating lymphocytes.
Paul Span
Annemarie Post and Paul Span from the new Radiotherapy & OncoImmunology lab of the department of Radiation Oncology, theme Women’s cancers, and colleagues investigated common features of tamoxifen resistance and radioresistance in breast cancer. Their findings will be published in the journal Clinical Cancer Research.
Treatment resistance is a main cause of adverse disease outcome in breast cancer patients. Therefore, this study aimed to identify common features of tamoxifen- and radioresistance in breast cancer cells in vitro and investigate relevant pathways in patient cohorts to establish the relevance of the identified pathways.
Both tamoxifen- and radioresistant breast cancer cells had increased expression levels of genes involved in type I interferon signaling, compared to non-resistant cells. IFN-stimulated genes (ISGs) were induced in a dose-dependent and time-dependent manner after tamoxifen treatment and irradiation. Tamoxifen treatment also led to ssDNA presence in the cytoplasm, a phenomenon that has already been described for irradiation and is known to induce expression of ISGs.
Several breast cancer patient cohorts were analyzed to investigate the relation of ISG expression with treatment sensitivity. In one cohort, high expression levels of ISGs were found in the primary tumor in around half of the patients. This was associated with a tumor infiltrating lymphocyte expression signature, while the ISGs were also expressed by the tumor cells themselves. Importantly, the expression of ISGs correlated to outcome in breast cancer patients treated with adjuvant tamoxifen or radiotherapy, but not in systemically untreated patients or chemotherapy-treated patients.
These data indicate that expression of ISGs by tumor cells is involved in acquired, treatment-induced resistance to tamoxifen and radiotherapy, and might play a role in intrinsic resistance via interaction with tumor infiltrating lymphocytes.
Paul Span
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