Estrogen induces c-Kit and an aggressive phenotype in a model of invasive lobular breast cancer.
Estrogen induces c-Kit and an aggressive phenotype in a model of invasive lobular breast cancer.
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DOI：
10.1038/s41389-017-0002-x
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发表时间：
2017-11-27
期刊：
影响因子：
6.2
通讯作者：
Jacobsen BM
中科院分区：
文献类型：
--
作者：
Harrell JC;Shroka TM;Jacobsen BM
在乳腺癌的分子亚型中，有腔(A或B)雌激素受体阳性(ER+)、HER2+和三阴性(基底样样)。除了分子亚型，还有18种组织学乳腺癌亚型按外观分类，包括浸润性小叶乳腺癌(ILC)，占所有乳腺癌的8%-15%，主要是ER+肿瘤。我们使用了一种新的ER+ILC模型，称为BCK4。为了确定我们的ILC模型中雌激素调节的基因，我们使用基因表达阵列检测了补充或不补充雌激素的小鼠的BCK4异种移植瘤。体内约有3000个基因受雌激素调控。对BCK4来源的肿瘤与ER+和ER-乳腺癌细胞系进行的等级聚类分析表明，雌激素治疗的BCK4肿瘤组ER-乳腺癌最有可能是由于高增殖分数，而来自添加纤维素的小鼠的肿瘤更多地与ER+乳腺肿瘤细胞有关。为了阐明BCK4细胞在体外受雌激素调控的基因，我们使用Illumina阵列进行了BCK4细胞株的表达谱分析，在体外进行了雌激素处理或不处理的处理。在BCK4细胞和移植瘤中，雌激素调控了一组~200个重叠的基因，通路分析表明c-Kit通路可能是抑制雌激素诱导的增殖的靶点。随后的研究发现，使用甲磺酸伊马替尼(Gleevec®)抑制c-Kit活性在体外阻断雌激素对BCK4肿瘤和BCK4细胞的刺激作用，与抗雌激素药物FUVESTRAN(FASLODEX®)一样有效。使用shRNA减少c-Kit的表达也减少了基线和雌激素在体外和体内诱导的增殖。这些研究首次表明，c-Kit抑制是靶向c-Kit+ILC的有效途径。
Among the molecular subtypes of breast cancer are luminal (A or B) estrogen receptor positive (ER+), HER2+, and triple negative (basal-like). In addition to the molecular subtypes, there are 18 histologic breast cancer subtypes classified on appearance, including invasive lobular breast carcinoma (ILC), which are 8–15% of all breast cancers and are largely ER+ tumors. We used a new model of ER+ ILC, called BCK4. To determine the estrogen regulated genes in our ILC model, we examined BCK4 xenograft tumors from mice supplemented with or without estrogen using gene expression arrays. Approximately 3000 genes were regulated by estrogen in vivo. Hierarchical cluster analyses of the BCK4 derived tumors compared with ER+ and ER- breast cancer cell lines show the estrogen treated BCK4 tumors group with ER- breast cancers most likely due to a high proliferation score, while tumors from cellulose supplemented mice were more related to ER+ breast tumor cells. To elucidate genes regulated in vitro by estrogen in BCK4 cells, we performed expression profiling using Illumina arrays of the BCK4 cell line, treated with or without estrogen in vitro. A set of ~200 overlapping genes were regulated by estrogen in the BCK4 cell line and xenograft tumors, and pathway analysis revealed that the c-Kit pathway might be a target to reduce estrogen-induced proliferation. Subsequent studies found that inhibition of c-Kit activity using imatinib mesylate (Gleevec®) blocked estrogen mediated stimulation of BCK4 tumors and BCK4 cells in vitro as effectively as the anti-estrogen fulvestrant (Faslodex®). Decreased expression of c-Kit using shRNA also decreased baseline and estrogen induced proliferation in vitro and in vivo. These studies are the first to indicate that c-Kit inhibition is an effective approach to target c-Kit+ ILC.
影响因子：
3.8
作者：
Badtke, Melanie M.;Jambal, Purevsuren;Dye, Wendy W.;Spillman, Monique A.;Post, Miriam D.;Horwitz, Kathryn B.;Jacobsen, Britta M.
通讯作者：
Jacobsen, Britta M.