The rearranged during transfection/papillary thyroid carcinoma tyrosine kinase is an estrogen-dependent gene required for the growth of estrogen receptor positive breast cancer cells.
The rearranged during transfection/papillary thyroid carcinoma tyrosine kinase is an estrogen-dependent gene required for the growth of estrogen receptor positive breast cancer cells.
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DOI：
10.1007/s10549-011-1775-9
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发表时间：
2012-06
影响因子：
3.8
通讯作者：
Brown, Powel H.
中科院分区：
文献类型：
--
作者：
Wang, Chunyu;Mayer, Julie Ann;Mazumdar, Abhijit;Brown, Powel H.
关键词：
甲状腺癌/乳头状癌(RET/PTC)中的酪氨酸激酶基因重排与甲状腺癌的发生密切相关。我们和其他人最近的研究表明，乳腺癌细胞中RET/PTC激酶的表达是由雌激素诱导的。鉴于雌激素调控基因在乳腺癌发病机制中的重要作用，我们研究了RET/PTC激酶在乳腺癌细胞中的表达、调控和功能。我们发现，在乳腺癌细胞和肿瘤标本中，RET/PTC激酶的表达与ER的表达有关，在ER阳性的乳腺癌患者中，RET/PTC激酶的表达与预后不良有关。我们发现雌激素以雌激素受体(ER)依赖的方式在乳腺癌细胞中快速诱导RET/PTC激酶的表达，并且这种诱导是通过转录调控机制实现的。利用记者实验、小干扰RNA(SiRNA)实验和染色质免疫沉淀(ChIP)实验，我们证明了ER和叉头盒A1(FOXA1)转录因子之间的串扰在调节RET/PTC激酶表达中的必要性。在功能研究中，雌激素刺激诱导的RET/PTC激酶表达增加导致多个下游信号通路的磷酸化水平升高。相反，RET/PTC表达的下调与这些相同的激酶信号通路的抑制有关，事实上，降低了雌激素对ER阳性乳腺癌细胞增殖的刺激作用。这些结果证明了ER和FOXA1转录因子串扰调节RET/PTC激酶表达的新途径，并证明RET/PTC激酶是ER阳性乳腺癌细胞增殖的关键调节因子。综上所述，我们的研究提示，RET/PTC激酶可能成为ER阳性乳腺癌预防和治疗的一种新的预后生物标志物和治疗靶点。
The rearranged during transfection/papillary thyroid carcinoma (RET/PTC) tyrosine kinase is an oncogene implicated in the tumorigenesis of thyroid cancer. Recent studies by us and others have shown that RET/PTC kinase expression is induced by estrogen in breast cancer cells. Due to the critical involvement of estrogen-regulated genes in the pathogenesis of breast cancer, we investigated the expression, regulation and function of RET/PTC kinase in breast cancer cells. We found that RET/PTC kinase expression correlates with ER expression in breast cancer cells and tumor specimens, and that RET/PTC kinase expression is associated with a poor prognosis in ER-positive breast cancer patients. We found that estrogen rapidly induces RET/PTC kinase expression in an estrogen receptor (ER)-dependent manner in breast cancer cells and that this induction is through a transcriptional regulatory mechanism. Using reporter assays, small interfering RNA (siRNA) assays, and chromatin immunoprecipitation (ChIP) assays, we demonstrated the necessity of crosstalk between ER and the forkhead box A1 (FOXA1) transcription factor in regulating RET/PTC kinase expression. In functional studies, increased expression of RET/PTC kinase induced by estrogen stimulation resulted in elevated phosphorylation of multiple downstream kinase signaling pathways. Conversely, knockdown of RET/PTC expression was associated with the inhibition of these same kinase signaling pathways, and, in fact, decreased the stimulatory effect of estrogen on the proliferation of ER-positive breast cancer cells. These results demonstrate a novel pathway of ER and FOXA1 transcription factor crosstalk in regulating RET/PTC kinase expression, and demonstrate that RET/PTC kinase is a critical regulator for the proliferation of ER-positive breast cancer cells. Taken together, our study suggests that RET/PTC kinase may serve as a novel prognostic biomarker and therapeutic target for prevention and treatment of ER-positive breast cancer.
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