Although reports implicate radioresistance as an important obstacle for the management of breast cancer, its molecular mechanism is elusive. Herein, we found that high HDGF levels are expressed significantly in breast cancer and exhibit a positive association with poor survival prognosis. Heparin-binding growth factor (HDGF) was upregulated in radioresistant breast cancer cells, however, its knockdown could reduce breast cancer radioresistant both in vitro and in vivo. Additionally, the binding of RXRα to HDGF promoter blocked HDGF transcriptional activity, consequently inhibiting breast cancer radioresistance. The enhanced radioresistant activity of HDGF is induced by TKT and STAT3, impacting the STAT3-Tyr705 and STAT3-Ser727 phosphorylation and STAT3 transcriptional activity. Notably, HDGF depletion renders radioresistant hypersensitive to the drug that targets STAT3 phosphorylation. This article demonstrates the novel function of HDGF as a promising molecular target for predicting radioresistance in breast cancer.

中文翻译：

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肝素结合生长因子 (HDGF) 通过激活 STAT3 信号通路驱动乳腺癌的放射抗性

尽管有报道暗示放射抗性是乳腺癌治疗的一个重要障碍，但其分子机制尚不清楚。在这里，我们发现高 HDGF 水平在乳腺癌中显着表达，并与较差的生存预后呈正相关。肝素结合生长因子 (HDGF) 在抗辐射的乳腺癌细胞中上调，然而，其敲低可以降低体外和体内乳腺癌的抗辐射性。此外，RXRα 与 HDGF 启动子的结合阻断了 HDGF 转录活性，从而抑制了乳腺癌的放射抗性。HDGF 增强的抗辐射活性由 TKT 和 STAT3 诱导，影响 STAT3-Tyr705 和 STAT3-Ser727 磷酸化和 STAT3 转录活性。尤其，HDGF 耗竭使放射抗性对靶向 STAT3 磷酸化的药物过敏。本文展示了 HDGF 作为预测乳腺癌放射抗性的有希望的分子靶标的新功能。