Tumor microenvironmental growth factors induce long-term estrogen deprivation resistance in breast cancer.
Tumor microenvironmental growth factors induce long-term estrogen deprivation resistance in breast cancer.
复制标题
肿瘤微环境生长因子诱导乳腺癌长期雌激素剥夺抵抗。
DOI：
10.1007/s12282-019-00978-z
复制
发表时间：
2019
期刊：
影响因子：
4
通讯作者：
Hayashi S
中科院分区：
文献类型：
--
作者：
Tsuboi K;Uematsu C;Yamaguchi Y;Niwa T;Hayashi S
背景激素治疗是治疗腔样乳腺癌的有效方法。芳香化酶抑制剂（AI）广泛用于雌激素受体阳性的绝经后乳腺癌。然而，耐药性发生并成为严重的临床问题。在一般情况下，癌症的进展强烈依赖于肿瘤微环境，这可能，因此，也有助于发展AI resistance.MethodsWe评估肿瘤微环境衍生的因素与AI阻力使用典型的雌激素受体阳性乳腺癌细胞系。我们建立了肿瘤微环境依赖的AI耐药模型，并阐明了潜在的mechanism.ResultsT-47 D细胞有较高的依赖微环境衍生的因素，如雌激素或生长因子，比MCF-7细胞的生存。因此，我们使用T-47 D细胞评估了肿瘤微环境生长因子与AI抗性的关系。我们建立了三个耐药细胞系（V1，V2和V3），生存雌激素剥夺和生长因子补充条件。这些细胞系缺乏雌激素受体α表达和雌激素依赖性生长。在6种代表性生长因子中，表皮生长因子的影响最大。在这些模型中，与亲本细胞系相比，HER 2蛋白在没有基因扩增的情况下过表达，并且细胞内磷酸化途径被激活。分子靶向抑制剂显示，V1和V2主要依赖于PI 3 K通路的生存，而V3依赖于MAPK pathway.ConclusionsThis study demonstrates the importance of tumor microenvironment-derived factors for the development of AI resistance.这些抗性模型没有利用相同的抗性机制，这表明灵活的策略在克服抗性方面是必不可少的。
BackgroundHormonal therapy is an effective treatment for luminal-like breast cancer. Aromatase inhibitor (AI) is widely used for estrogen receptor-positive, postmenopausal breast cancers. However, resistance is occurred and becomes a serious clinical concern. In general, progression of cancer strongly depends on tumor microenvironment, which may, therefore, also contribute to the development of AI resistance.MethodsWe evaluated tumor microenvironment-derived factors with respect to AI resistance using typical estrogen receptor-positive breast cancer cell lines. We established tumor microenvironment-dependent AI-resistant models and elucidated the underlying mechanisms.ResultsT-47D cells had a higher dependence on microenvironment-derived factors, such as estrogen or growth factors, for survival than MCF-7 cells. We, therefore, evaluated tumor microenvironment growth factors with respect to AI resistance using T-47D cells. We established three resistant cell lines (V1, V2, and V3) that survived estrogen deprivation and growth factor-supplemented conditions. These cell lines were deficient in estrogen receptor α expression and estrogen-dependent growth. Among six representative growth factors, epidermal growth factor was the most influential. In these models, HER2 protein was overexpressed without gene amplification and intracellular phosphorylation pathways were activated compared to parental cell lines. Molecular targeting inhibitors revealed that V1 and V2 primarily rely on the PI3 K pathway for survival, whereas V3 relies on the MAPK pathway.ConclusionsThis study demonstrates the importance of tumor microenvironment-derived factors for the development of AI resistance. These resistant models did not utilize the same resistance mechanism, suggesting that flexible strategies are essential in conquering resistance.