Abstract
Breast cancer is the most common cancer for women in Taiwan and post-lumpectomy radiotherapy is one of the therapeutic strategies for this malignancy. Although the 10-year overall survival of breast cancer patients is greatly improved by radiotherapy, the locoregional recurrence is around 10% and triple negative breast cancers (TNBCs) are at a high risk for relapse. The aim of this paper is to understand the mechanisms of radioresistance in breast cancers which may facilitate the development of new treatments in sensitizing breast cancer toward radiation therapy. Tribbles homolog 3 (TRIB3) is a pseudokinase protein and known to function as a protein scaffold within cells. It has been reported that higher TRIB3 expression is a poor prognostic factor in breast cancer patients with radiotherapy. In this study, we investigate the involvement of TRIB3 in the radiation response of TNBC cells. We first found that the expression of TRIB3 and the activation of Notch1, as well as Notch1 target genes, increased in two radioresistant TNBC cells. Knockdown of TRIB3 in radioresistant MDA-MB-231 TNBC cells decreased Notch1 activation, as well as the CD24-CD44+ cancer stem cell population, and sensitized cells toward radiation treatment. The inhibitory effects of TRIB3 knockdown in self-renewal or radioresistance could be reversed by forced expression of the Notch intracellular domain. We also observed an inhibition in cell growth and accumulated cells in the G0/G1 phase in radioresistant MDA-MB-231 cells after knockdown of TRIB3. With immunoprecipitation and mass spectrometry analysis, we found that, BCL2-associated transcription factor 1 (BCLAF1), BCL2 interacting protein 1 (BNIP1), or DEAD-box helicase 5 (DDX5) were the possible TRIB3 interacting proteins and immunoprecipitation data also confirmed that these proteins interacted with TRIB3 in radioresistant MDA-MB-231 cells. In conclusion, the expression of TRIB3 in radioresistant TNBC cells participated in Notch1 activation and targeted TRIB3 expression may be a strategy to sensitize TNBC cells toward radiation therapy.
Highlights
Breast cancer is the most common cancer for women in Taiwan
With quantitative real time (RT)-PCR and Western blot analysis, we found the expression of Tribbles homolog 3 (TRIB3) and the activation of NOTCH1 was increased in radioresistant triple negative breast cancers (TNBCs) cells
It has been reported that TRIB3 regulated Notch1 activation in lung cancer cells [13] and Notch1 activation is known to lead to radioresistance of TNBCs [14]
Summary
Breast cancer is the most common cancer for women in Taiwan. Surgery remains the most important primary treatment for breast cancer, which is to remove most of the cancer cells from the breast. Radiotherapy was added for breast cancer patients who have higher local recurrence rate after the surgery in order to further improve the local control and overall survival. Cancer Trialists’ Collaborative Group (EBCTCG), who conducted a meta-analysis to evaluate the effect of radiotherapy for women receiving breast conserving surgery, reported that adding radiotherapy to patients after the breast conserving surgery can reduce the 10-year risk of locoregional recurrence rate from 25% to 8% [2]. Despite the use of radiotherapy in breast cancer treatment, the locoregional recurrence rate in 10 years was still among 4–13% for different patient populations [3]. Among the subtypes of breast cancer, triple negative breast cancers (TNBCs), which express very low levels or are negative for ER, PR, and HER2, are significantly associated with a high risk of locoregional recurrence following radiotherapy [5]. TNBCs are considered to be more insensitive to radiotherapy than other subtypes of breast cancer [5] and the molecular mechanisms in TNBC cells resistant to radiotherapy are not completely understood
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