Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
Cell Cycle. 2012 Jul 15;11(14):2756-61. doi: 10.4161/cc.21195.
To model the heterogeneity of breast cancer as observed in the clinic, we employed an ex vivo model of breast tumor tissue. This methodology maintained the histological integrity of the tumor tissue in unselected breast cancers, and importantly, the explants retained key molecular markers that are currently used to guide breast cancer treatment (e.g., ER and Her2 status). The primary tumors displayed the expected wide range of positivity for the proliferation marker Ki67, and a strong positive correlation between the Ki67 indices of the primary and corresponding explanted tumor tissues was observed. Collectively, these findings indicate that multiple facets of tumor pathophysiology are recapitulated in this ex vivo model. To interrogate the potential of this preclinical model to inform determinants of therapeutic response, we investigated the cytostatic response to the CDK4/6 inhibitor, PD-0332991. This inhibitor was highly effective at suppressing proliferation in approximately 85% of cases, irrespective of ER or HER2 status. However, 15% of cases were completely resistant to PD-0332991. Marker analyses in both the primary tumor tissue and the corresponding explant revealed that cases resistant to CDK4/6 inhibition lacked the RB-tumor suppressor. These studies provide important insights into the spectrum of breast tumors that could be treated with CDK4/6 inhibitors, and defines functional determinants of response analogous to those identified through neoadjuvant studies.
为了模拟临床上观察到的乳腺癌异质性，我们采用了体外乳腺癌肿瘤组织模型。这种方法保持了未经选择的乳腺癌肿瘤组织的组织学完整性，重要的是，这些外植体保留了目前用于指导乳腺癌治疗的关键分子标志物（如 ER 和 Her2 状态）。原发肿瘤显示出预期的 Ki67 增殖标志物的广泛阳性表达，并且在原发和相应的离体肿瘤组织之间观察到 Ki67 指数之间存在强烈的正相关。这些发现表明，肿瘤病理生理学的多个方面在这种体外模型中得到了重现。为了研究这种临床前模型在告知治疗反应决定因素方面的潜力，我们研究了细胞周期蛋白依赖性激酶 4/6（CDK4/6）抑制剂 PD-0332991 的细胞抑制反应。该抑制剂在大约 85%的病例中非常有效地抑制增殖，而与 ER 或 Her2 状态无关。然而，有 15%的病例对 PD-0332991 完全耐药。在原发肿瘤组织和相应的离体组织中进行的标志物分析表明，对 CDK4/6 抑制耐药的病例缺乏 RB 肿瘤抑制因子。这些研究为可以用 CDK4/6 抑制剂治疗的乳腺癌肿瘤谱提供了重要的见解，并定义了与新辅助研究中确定的类似的反应功能决定因素。
