High expression of human epidermal factor receptor 2 (HER2) is directly related to tumor progression, malignancy and drug resistance in HER2-positive breast cancer (HER2-PBC). The major limitation of current anti-HER2 therapies is that they cannot reduce the levels of HER2 protein. Here, we investigated the effect of acetyltanshinone IIA (ATA) in lapatinib-resistant HER2-PBC cells. Our data showed that ATA exhibited more potent effects than lapatinib against drug-resistant HER2-PBC cells in terms of (1) inhibiting cell growth, (2) reducing phosphorylated and total HER2 levels, (3) inhibiting tumor xenograft growth in nude mice, and (4) reducing HER2 protein levels in tumor xenografts. A mechanistic study revealed that ATA promoted HER2 degradation via increasing c-Cbl and CHIP-mediated HER2 ubiquitination and subsequent HER2 degradation by the proteasome or lysosome. ATA also reduced the levels of other tyrosine kinase receptors (TKRs), such as HER3, IGF-1R and MET, in lapatinib-resistant cells. Our findings suggest that direct degradation of HER2 and other TKRs can be an effective strategy for combatting drug resistance. They also indicate the potential utilization of ATA in treating breast cancer that is resistant or nonresponsive to current HER2-targeted therapies.

人表皮因子受体2（HER2）的高表达与HER2阳性乳腺癌（HER2-PBC）中的肿瘤进展，恶性和耐药性直接相关。当前抗HER2疗法的主要局限性在于它们不能降低HER2蛋白的水平。在这里，我们研究了乙酰丹参酮IIA（ATA）在对拉帕替尼耐药的HER2-PBC细胞中的作用。我们的数据显示，就（1）抑制细胞生长，（2）降低磷酸化和总HER2水平，（3）抑制裸鼠的肿瘤异种移植生长而言，ATA比拉帕替尼对耐药性HER2-PBC细胞具有更强的作用。 （4）降低肿瘤异种移植物中的HER2蛋白水平。一项机械研究表明，ATA通过增加c-Cbl和CHIP介导的HER2泛素化并随后由蛋白酶体或溶酶体降解HER2来促进HER2降解。ATA还降低了对拉帕替尼耐药细胞中其他酪氨酸激酶受体（TKR）的水平，例如HER3，IGF-1R和MET。我们的发现表明，HER2和其他TKR的直接降解可能是对抗耐药性的有效策略。他们还表明了ATA在治疗对当前HER2靶向疗法有抗药性或无反应的乳腺癌中的潜在用途。我们的发现表明，HER2和其他TKR的直接降解可能是抵抗耐药性的有效策略。他们还表明了ATA在治疗对当前HER2靶向疗法有抗药性或无反应的乳腺癌中的潜在用途。我们的发现表明，HER2和其他TKR的直接降解可能是抵抗耐药性的有效策略。他们还表明了ATA在治疗对当前HER2靶向疗法有抗药性或无反应的乳腺癌中的潜在用途。