Most women diagnosed with breast cancer (BC) have estrogen receptor alpha-positive (ER+) disease. The current mouse models of ER+ BC often rely on exogenous estrogen to encourage metastasis, which modifies the immune system and the function of some tissues like bone. Other studies use genetically modified or immunocompromised mouse strains, which do not accurately replicate the clinical disease. To create a model of antiestrogen responsive BC with spontaneous metastasis, we developed a mouse model of 4T1.2 triple-negative (TN) breast cancer with virally transduced ER expression that metastasizes spontaneously without exogenous estrogen stimulation and is responsive to antiestrogen drugs. Our mouse model exhibited upregulated ER-responsive genes and multi-organ metastasis without exogenous estrogen administration. Additionally, we developed a second TN BC cell line, E0771/bone, to express ER, and while it expressed ER-responsive genes, it lacked spontaneous metastasis to clinically important tissues. Following antiestrogen treatment (tamoxifen, ICI 182,780, or vehicle control), 4T1.2- and E0771/bone-derived tumor volumes and weights were significantly decreased, exemplifying antiestrogen responsivity in both cell lines. This 4T1.2 tumor model, which expresses the estrogen receptor, metastasizes spontaneously, and responds to antiestrogen treatment, will allow for further investigation into the biology and potential treatment of metastasis.
大多数被诊断为乳腺癌（BC）的患者为雌激素受体α阳性（ER+）。目前ER+乳腺癌的小鼠模型常依赖外源性雌激素促进转移，这会改变免疫系统及骨骼等组织的功能。其他研究则使用基因改造或免疫缺陷小鼠品系，这些模型无法准确复现临床疾病。为建立具有自发转移能力的抗雌激素响应型乳腺癌模型，我们开发了一种4T1.2三阴性（TN）乳腺癌小鼠模型，该模型通过病毒转导表达ER，无需外源性雌激素刺激即可自发转移，并对抗雌激素药物产生响应。该小鼠模型在不给予外源性雌激素的情况下，表现出ER响应基因的上调及多器官转移。此外，我们构建了第二个表达ER的TN乳腺癌细胞系E0771/bone，该细胞系虽能表达ER响应基因，但缺乏向临床重要组织的自发转移能力。经抗雌激素治疗（他莫昔芬、ICI 182,780或载体对照）后，4T1.2和E0771/bone来源的肿瘤体积与重量均显著减小，证明两种细胞系均具有抗雌激素响应性。这种表达雌激素受体、能自发转移且对抗雌激素治疗产生应答的4T1.2肿瘤模型，将为转移机制研究与潜在治疗策略探索提供重要工具。
A Novel Metastatic Estrogen Receptor-Expressing Breast Cancer Model with Antiestrogen Responsiveness
肿瘤(癌症)患者之家