Roßwag Sven, Cotarelo Cristina L, Pantel Klaus, Riethdorf Sabine, Sleeman Jonathan P, Schmidt Marcus, Thaler Sonja
European Center for Angioscience, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
Institute of Pathology, University Medical Center of Heinrich-Heine University, 40225 Duesseldorf, Germany.
Cancers (Basel). 2021 Apr 10;13(8):1810. doi: 10.3390/cancers13081810.
Mechanisms of acquired endocrine resistance and late recurrence in patients with ER+/HER2- breast cancer are complex and not fully understood. Here, we evaluated mechanisms of acquired resistance in circulating tumor cells (CTCs) from an ER+/HER2- breast cancer patient who initially responded but later progressed under endocrine treatment. We found a switch from ERα-dependent to HER2-dependent and ERα-independent expression of FOXM1, which may enable disseminated ER+/HER2- cells to re-initiate tumor cell growth and metastasis formation in the presence of endocrine treatment. Our results also suggest a role for HER2 in resistance, even in ER+ breast cancer cells that have neither HER2 amplification nor activating HER2 mutations. We found that NFkB signaling sustains HER2 and FOXM1 expression in CTCs in the presence of ERα inhibitors. Inhibition of NFkB signaling blocked expression of HER2 and FOXM1 in the CTCs, and induced apoptosis. Thus, targeting of NFkB and FOXM1 might be an efficient therapeutic approach to prevent late recurrence and to treat endocrine resistance. Collectively our data show that CTCs from patients with endocrine resistance allow mechanisms of acquired endocrine resistance to be delineated, and can be used to test potential drug regimens for combatting resistance.
雌激素受体阳性/人表皮生长因子受体2阴性（ER+/HER2-）乳腺癌患者获得性内分泌耐药及晚期复发的机制复杂，尚未完全明确。在此，我们评估了一名ER+/HER2-乳腺癌患者循环肿瘤细胞（CTC）中的获得性耐药机制，该患者最初对内分泌治疗有反应，但随后病情进展。我们发现叉头框蛋白M1（FOXM1）的表达从雌激素受体α（ERα）依赖型转变为HER2依赖型且不依赖ERα，这可能使播散的ER+/HER2-细胞在内分泌治疗存在的情况下重新启动肿瘤细胞生长和转移形成。我们的结果还表明HER2在耐药中发挥作用，即使在既无HER2扩增也无激活HER2突变 的ER+乳腺癌细胞中也是如此。我们发现，在存在ERα抑制剂的情况下，核因子κB（NFkB）信号传导维持CTC中HER2和FOXM1的表达。抑制NFkB信号传导可阻断CTC中HER2和FOXM1的表达，并诱导细胞凋亡。因此，靶向NFkB和FOXM1可能是预防晚期复发和治疗内分泌耐药的有效治疗方法。我们的数据总体表明，来自内分泌耐药患者的CTC能够描绘获得性内分泌耐药的机制，并可用于测试对抗耐药性的潜在药物方案。
