Wang Yuanzhong, Tzeng Yen-Dun Tony, Chang Gregory, Wang Xiaoqiang, Chen Shiuan
Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, California, USA.
Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung City, Taiwan, Republic of China.
Endocr Relat Cancer. 2020 Dec;27(12):671-683. doi: 10.1530/ERC-20-0258.
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 EGF 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.
对芳香化酶抑制剂（AIs）产生获得性耐药是雌激素受体（ER）阳性乳腺癌内分泌治疗中的一个重大临床问题，而ER阳性乳腺癌占乳腺癌的大多数。尽管雌激素生成受到抑制，但ERα信号传导仍保持活跃，并在大多数对AI耐药的乳腺肿瘤中起关键作用。在此，我们发现双调蛋白（AREG），一种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耐药乳腺癌细胞中的ERα表达和信号传导至关重要。AREG在ER + AI耐药乳腺癌细胞中失调且对细胞活力至关重要，并且AREG在激素反应性乳腺癌细胞中的异位表达促进了内分泌耐药。RNA测序和反向蛋白质阵列分析表明，AREG通过激活PI3K/Akt/mTOR信号传导以及上调叉头框M1（FOXM1）和血清及糖皮质激素诱导激酶3（SGK3）的表达来维持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以前未被认识的作用，并确立了AREG-ERα相互作用作为乳腺癌获得性AI耐药的驱动因素。
