Interferon-stimulated genes are involved in cross-resistance to radiotherapy in tamoxifen-resistant breast cancer

Purpose: Treatment resistance is the main cause of adverse disease outcome in breast cancer patients. Here, we aimed to investigate common features in tamoxifen-resistant and radioresistant breast cancer, as tamoxifen-resistant breast cancer cells are cross-resistant to irradiation in vitro. Experimental Design: RNA sequencing of tamoxifen-resistant and radioresistant breast cancer cells was performed and validated by quantitative PCR. Pathways were further investigated in vitro and in breast cancer patient cohorts to establish their relation with treatment resistance. Results: Both tamoxifen-resistant and radioresistant breast cancer cells had increased expression levels of genes involved in type I IFN signaling compared with nonresistant cells. IFN-stimulated genes (ISG) 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, which is known to induce expression of ISGs, a phenomenon that has already been described for irradiation. Moreover, in a breast cancer patient 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 (TIL) expression signature, although the ISGs were also expressed by the tumor cells themselves. Importantly, the expression of ISGs correlated with outcome in breast cancer patients treated with adjuvant tamoxifen or radiotherapy, but not in systemically untreated patients or chemotherapy-treated patients. Conclusions: Our 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 TILs.

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