Triple-negative breast cancer (TNBC) lacks significant expression of the estrogen receptor, the progesterone receptor, and of human epidermal growth factor receptor. It is the most aggressive and malignant of all breast cancers, and for which, there are currently no effective targeted therapies. We have shown previously that the RecQ helicase family member RECQL5 is essential for the proliferation and survival of TNBC cells; however, the mechanism of its involvement in cell viability has not been shown. Here, we report that the expression of RecQ family helicases, including RECQL5, is regulated by the deubiquitinase USP28. We found using genetic depletion or a small molecule inhibitor that like RECQL5, USP28 is also essential for TNBC cells to proliferate in vitro and in vivo. Compromising the function of USP28 by shRNA knockdown or the inhibitor caused TNBC cells to arrest in S/G2 phases, concurrent with DNA-damage checkpoint activation. We further showed that the small molecule inhibitor of USP28 displayed anti-tumor activity against xenografts derived from TNBC cells. Our results suggest that USP28 could be a potential therapeutic target for triple negative breast cancer.

中文翻译：

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去泛素化酶 USP28 可稳定 RecQ 家族解旋酶的表达并维持三阴性乳腺癌细胞的活力。

三阴性乳腺癌 (TNBC) 缺乏雌激素受体、孕激素受体和人表皮生长因子受体的显着表达。它是所有乳腺癌中最具侵袭性和恶性的，目前尚无有效的靶向治疗方法。我们之前已经表明，RecQ 解旋酶家族成员 RECQL5 对于 TNBC 细胞的增殖和存活至关重要。然而，尚未显示其参与细胞活力的机制。在这里，我们报告 RecQ 家族解旋酶（包括 RECQL5）的表达受去泛素酶 USP28 的调节。我们发现使用基因耗竭或像 RECQL5 一样的小分子抑制剂，USP28 对于 TNBC 细胞在体外和体内增殖也是必不可少的。通过 shRNA 敲低或抑制剂损害 USP28 的功能导致 TNBC 细胞在 S/G2 期停滞，同时 DNA 损伤检查点激活。我们进一步表明，USP28 的小分子抑制剂对源自 TNBC 细胞的异种移植物表现出抗肿瘤活性。我们的研究结果表明，USP28 可能是三阴性乳腺癌的潜在治疗靶点。