Estrogen-regulated feedback loop limits the efficacy of estrogen receptor-targeted breast cancer therapy.
Estrogen-regulated feedback loop limits the efficacy of estrogen receptor-targeted breast cancer therapy.
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雌激素调节的反馈回路限制了雌激素受体靶向乳腺癌治疗的功效。
DOI：
10.1073/pnas.1722617115
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发表时间：
2018-07-31
影响因子：
11.1
通讯作者：
Brown M
中科院分区：
文献类型：
--
作者：
Xiao T;Li W;Wang X;Xu H;Yang J;Wu Q;Huang Y;Geradts J;Jiang P;Fei T;Chi D;Zang C;Liao Q;Rennhack J;Andrechek E;Li N;Detre S;Dowsett M;Jeselsohn RM;Liu XS;Brown M
雌激素受体阳性（ER+）乳腺癌采用内分泌疗法治疗，尽管在晚期疾病中几乎总是会出现治疗耐药性。使用全基因组 CRISPR 筛选，我们鉴定了因丢失而产生内分泌抗性的基因，以及克服这种抗性的合成致死漏洞。这些发现揭示了雌激素诱导的负反馈回路限制了 ER+ 肿瘤的生长，从而限制了抑制 ER 的疗法的疗效，并提出了一种以前未被重视的克服内分泌抵抗的治疗途径。晚期雌激素受体阳性（ER+）乳腺癌中总是会出现内分泌治疗耐药，但其潜在机制在很大程度上尚不清楚。我们已经确定 C 端 SRC 激酶 (CSK) 是先前未被重视的负反馈循环中的关键节点，该循环限制了当前 ER 靶向疗法的功效。雌激素直接驱动 ER+ 乳腺癌中的 CSK 表达。在低 CSK 水平下，就像对内分泌治疗耐药且预后最差的 ER+ 乳腺癌患者一样，p21 蛋白激活激酶 2 (PAK2) 被激活并驱动不依赖于雌激素的生长。 PAK2 过度表达还与内分泌治疗耐药和较差的临床结果相关，PAK2 抑制剂与 ER 拮抗剂的组合可协同抑制乳腺肿瘤的生长。内分泌治疗耐药乳腺癌的临床方法必须克服雌激素诱导的负反馈环路的丧失，这种负反馈环路通常会限制 ER+ 肿瘤的生长。
Estrogen receptor-positive (ER+) breast cancer is treated with endocrine therapies, although therapeutic resistance almost invariably develops in advanced disease. Using genome-wide CRISPR screens, we identified genes whose loss confers endocrine resistance, as well as synthetic lethal vulnerabilities to overcome such resistance. These findings reveal an estrogen-induced negative feedback loop that constrains the growth of ER+ tumors, thereby limiting the efficacy of therapies that inhibit ER, and suggest a previously unappreciated therapeutic route to overcoming endocrine resistance. Endocrine therapy resistance invariably develops in advanced estrogen receptor-positive (ER+) breast cancer, but the underlying mechanisms are largely unknown. We have identified C-terminal SRC kinase (CSK) as a critical node in a previously unappreciated negative feedback loop that limits the efficacy of current ER-targeted therapies. Estrogen directly drives CSK expression in ER+ breast cancer. At low CSK levels, as is the case in patients with ER+ breast cancer resistant to endocrine therapy and with the poorest outcomes, the p21 protein-activated kinase 2 (PAK2) becomes activated and drives estrogen-independent growth. PAK2 overexpression is also associated with endocrine therapy resistance and worse clinical outcome, and the combination of a PAK2 inhibitor with an ER antagonist synergistically suppressed breast tumor growth. Clinical approaches to endocrine therapy-resistant breast cancer must overcome the loss of this estrogen-induced negative feedback loop that normally constrains the growth of ER+ tumors.
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影响因子：
30.8
作者：
He, Housheng Hansen;Meyer, Clifford A.;Shin, Hyunjin;Bailey, Shannon T.;Wei, Gang;Wang, Qianben;Zhang, Yong;Xu, Kexin;Ni, Min;Lupien, Mathieu;Mieczkowski, Piotr;Lieb, Jason D.;Zhao, Keji;Brown, Myles;Liu, X. Shirley
通讯作者：
Liu, X. Shirley
影响因子：
11.2
作者：
Kang, Hyun-Jin;Lee, Min-Ho;Lee, Mi-Ock
通讯作者：
Lee, Mi-Ock
影响因子：
4.8
作者：
Jung, JH;Traugh, JA
通讯作者：
Traugh, JA
影响因子：
51.1
作者：
Finn, Richard S.;Crown, John P.;Slamon, Dennis J.
通讯作者：
Slamon, Dennis J.
影响因子：
56.9
作者：
KNAUS, UG;MORRIS, S;BOKOCH, GM
通讯作者：
BOKOCH, GM