Amphiregulin retains ERα expression in acquired aromatase inhibitor resistant breast cancer cells.
Amphiregulin retains ERα expression in acquired aromatase inhibitor resistant breast cancer cells.
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DOI：
10.1530/erc-20-0258
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发表时间：
2020-12
影响因子：
3.9
通讯作者：
Chen S
中科院分区：
文献类型：
--
作者：
Wang Y;Tzeng YT;Chang G;Wang X;Chen S
获得性芳香化酶抑制剂耐药是雌激素受体（ER）阳性乳腺癌内分泌治疗中的一个重要临床问题。尽管雌激素的产生受到抑制，但ERα信号仍然活跃，并在大多数耐AI乳腺肿瘤中发挥关键作用。在这里，我们发现双调蛋白（AREG），ERα转录靶点和表皮生长因子受体（EGFR）配体，对于维持获得性AI耐药乳腺癌细胞中ERα表达和信号传导至关重要。AREG在ER+ AI耐药乳腺癌细胞中是失调的并且对细胞活力至关重要，并且AREG在激素响应性乳腺癌细胞中的异位表达促进内分泌耐药。RNA测序和反相蛋白阵列分析显示，AREG通过激活PI 3 K/Akt/mTOR信号传导和上调叉头盒M1（FoxM 1）和血清和糖皮质激素诱导激酶3（SGK 3）表达来维持ERα表达和信号传导。我们的研究揭示了AREG在维持ERα表达和信号传导方面的一个先前未被认识到的作用，并建立了AREG-ERα串扰作为乳腺癌中获得性AI耐药的驱动因素。
Acquired resistance to aromatase inhibitors (AIs) is a significant clinical issue in endocrine therapy for estrogen receptor (ER) positive breast cancer which accounts for the majority of breast cancer. Despite estrogen production being suppressed, ERα signaling remains active and plays a key role in most AI-resistant breast tumors. Here, we found that amphiregulin (AREG), an ERα transcriptional target and epidermal growth factor receptor (EGFR) ligand, is crucial for maintaining ERα expression and signaling in acquired AI-resistant breast cancer cells. AREG was deregulated and critical for cell viability in ER+ AI-resistant breast cancer cells, and ectopic expression of AREG in hormone responsive breast cancer cells promoted endocrine resistance. RNA-sequencing and reverse phase protein array analyses revealed that AREG maintains ERα expression and signaling by activation of PI3K/Akt/mTOR signaling and upregulation of Forkhead Box M1 (FoxM1) and Serum- and glucocorticoid-inducible kinase 3 (SGK3) expression. Our study uncovers a previously unappreciated role of AREG in maintaining ERα expression and signaling, and establishes the AREG-ERα crosstalk as a driver of acquired AI resistance in breast cancer.