Marcho Lynn M, Coss Christopher C, Xu Menglin, Datta Jharna, Manouchehri Jasmine M, Cherian Mathew A
bioRxiv. 2024 Jan 15:2024.01.12.575428. doi: 10.1101/2024.01.12.575428.
Seventy percent of newly diagnosed breast cancers are estrogen receptor-α positive and HER2/neu negative [1]. First-line treatments incorporate endocrine therapy and cyclin-dependent kinase 4/6 inhibitors [2]. However, therapy resistance occurs in most patients [3-5]. Hence, there is an urgent need for effective second-line treatments. We previously showed that the potent estrogen receptor-β agonists, OSU-ERb-12 and LY500307, synergized with the selective estrogen receptor modulator, tamoxifen, in vitro. Furthermore, we showed that these compounds inhibited endocrine-resistant and cyclin-dependent kinase 4/6-inhibitor-resistant estrogen receptor α-positive cell lines in vitro [6]. Here, we used fulvestrant- and abemaciclib-resistant T47D-derived cell line xenografts to determine the efficacy of the combination of OSU-ERb-12 and LY500307 with tamoxifen in vivo.
Despite efficacy in vitro, treatments failed to reduce xenograft tumor volumes. Hence, we conclude that this treatment strategy lacks direct cancer cell-intrinsic cytotoxic efficacy in vivo.
新诊断的乳腺癌中70%为雌激素受体-α阳性且人表皮生长因子受体2/神经生长因子受体（HER2/neu）阴性[1]。一线治疗包括内分泌治疗和细胞周期蛋白依赖性激酶4/6抑制剂[2]。然而，大多数患者会出现治疗耐药[3-5]。因此，迫切需要有效的二线治疗方法。我们之前表明，强效雌激素受体-β激动剂OSU-ERb-12和LY500307在体外可与选择性雌激素受体调节剂他莫昔芬协同作用。此外，我们还表明这些化合物在体外可抑制内分泌耐药和细胞周期蛋白依赖性激酶4/6抑制剂耐药的雌激素受体α阳性细胞系[6]。在此，我们使用氟维司群和阿贝西利耐药的T47D衍生细胞系异种移植模型来确定OSU-ERb-12和LY500307与他莫昔芬联合使用在体内的疗效。
尽管在体外有疗效，但治疗未能减小异种移植瘤的体积。因此，我们得出结论，这种治疗策略在体内缺乏直接的癌细胞内在细胞毒性疗效。
