Tip30 deletion in MMTV-Neu mice leads to enhanced EGFR signaling and development of estrogen receptor-positive and progesterone receptor-negative mammary tumors.
Tip30 deletion in MMTV-Neu mice leads to enhanced EGFR signaling and development of estrogen receptor-positive and progesterone receptor-negative mammary tumors.
复制标题
DOI：
10.1158/0008-5472.can-10-3057
复制
发表时间：
2010-12-15
期刊：
影响因子：
11.2
通讯作者：
Xiao H
中科院分区：
文献类型：
--
作者：
Zhang C;Mori M;Gao S;Li A;Hoshino I;Aupperlee MD;Haslam SZ;Xiao H
雌激素受体阳性和孕激素受体阴性（ER+/PR-）乳腺癌占所有人类乳腺癌的15-25%，与ER+/PR+癌症相比，表现出更具侵袭性的恶性特征。然而，ER+/PR−乳腺癌发生的分子机制仍然难以捉摸。我们在这里表明，Tip 30缺失显着加速乳腺癌的MMTV-Neu小鼠模型中的乳腺肿瘤的发病。Tip 30 −/−/MMTV-Neu小鼠中出现的乳腺肿瘤仅为ER+/PR−。这些ER+/PR−肿瘤的生长不仅依赖于雌激素，还依赖于孕酮，尽管没有检测到PR。Tip 30主要表达于ER+乳腺上皮细胞（MEC），其缺失导致乳腺中磷酸化ER α（p-ERα）阳性细胞数量增加，并加速MMTV-Neu小鼠中Akt的激活。此外，我们发现Tip 30通过控制EGFR蛋白水平和信号转导的内吞下调来调节EGFR通路。总之，这些发现表明了一种新的机制，其中Tip 30的缺失与Neu激活协同作用，增强Akt信号的激活，导致ER+/PR−乳腺肿瘤的发展。
Estrogen receptor-positive and progesterone receptor-negative (ER+/PR−) breast cancers account for 15–25% of all human breast cancers and display more aggressive malignant characteristics compared to ER+/PR+ cancers. However, the molecular mechanism underlying development of ER+/PR− breast cancers still remains elusive. We show here that Tip30 deletion dramatically accelerated the onset of mammary tumors in the MMTV-Neu mouse model of breast cancer. The mammary tumors arising in Tip30−/−/MMTV-Neu mice were exclusively ER+/PR−. The growth of these ER+/PR− tumors depends not only on estrogen but also on progesterone despite the absence of detectable PR. Tip30 is predominantly expressed in ER+ mammary epithelial cells (MECs) and its deletion leads to an increase in the number of phospho-ERα (p-ERα) positive cells in mammary glands and accelerated activation of Akt in MMTV-Neu mice. Moreover, we found that Tip30 regulates the EGFR pathway through controlling endocytic downregulation of EGFR protein level and signaling. Together, these findings suggest a novel mechanism in which loss of Tip30 cooperates with Neu activation to enhance the activation of Akt signaling, leading to the development of ER+/PR− mammary tumors.