Insulin receptor substrate-1 (IRS-1) mediates progesterone receptor-driven stemness and endocrine resistance in oestrogen receptor+ breast cancer.
Insulin receptor substrate-1 (IRS-1) mediates progesterone receptor-driven stemness and endocrine resistance in oestrogen receptor+ breast cancer.
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DOI：
10.1038/s41416-020-01094-y
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发表时间：
2021-01
影响因子：
8.8
通讯作者：
Lange CA
中科院分区：
文献类型：
--
作者：
Dwyer AR;Truong TH;Kerkvliet CP;Paul KV;Kabos P;Sartorius CA;Lange CA
孕激素受体（PR）是内分泌反应的有效调节剂。在异常信号传导癌症背景下，磷酸化事件显著改变类固醇激素受体作用。在单细胞RNAseq后分析了携带ER+乳腺癌患者来源的异种移植物（PDX）的小鼠中原发性肿瘤和转移瘤的转录组。采用体外试验来描述内分泌抵抗和干性的机制。一个16基因磷酸化Ser 294 PR（p-PR）标志预测ER+乳腺癌预后不良。相对于原发性PDX肿瘤，转移性病变表达丰富的p-PR，并表现出激活的PR基因程序，PGR和IRS-1的表达升高。激活PR的乳腺癌模型失去了IGF 1 R的表达，获得了胰岛素超敏性和他莫昔芬不敏感性。活化的p-PR+乳腺癌细胞形成的肿瘤球增加，ALDH+和CD 24 −/CD 44群体扩大。E2诱导PR/IRS-1相互作用，并在含p-PR的转录复合物中将IGF 1 R β交换为IRS-1。抑制IRS-1或IR和诱导型IRS-1敲低减少了肿瘤球。管腔型B乳腺癌的内分泌抵抗模型在3D培养中诱导p-PR，并且需要PR和IRS-1来形成肿瘤球。磷酸化PR-B与IRS-1协同促进内分泌抵抗和干细胞样乳腺癌细胞的生长靶向磷酸-PR/IRS-1串扰可能会阻止内分泌抵抗的出现。
Progesterone receptors (PR) are potent modifiers of endocrine responses. In aberrant signalling cancer contexts, phosphorylation events dramatically alter steroid hormone receptor action. The transcriptomes of primary tumours and metastases in mice harbouring ER+ breast cancer patient-derived xenografts (PDXs) were analysed following single-cell RNAseq. In vitro assays were employed to delineate mechanisms of endocrine resistance and stemness. A 16-gene phospho-Ser294 PR (p-PR) signature predicted poor outcome in ER+ breast cancer. Relative to primary PDX tumours, metastatic lesions expressed abundant p-PR and exhibited an activated PR gene programme with elevated expression of PGR and IRS-1. Breast cancer models of activated PR lost the expression of IGF1R and acquired insulin hypersensitivity with tamoxifen insensitivity. Activated p-PR+ breast cancer cells formed increased tumourspheres with enlarged ALDH+ and CD24−/CD44 populations. E2 induced PR/IRS-1 interaction and exchange of IGF1Rβ for IRS-1 in p-PR-containing transcriptional complexes. Inhibition of IRS-1 or IR and inducible IRS-1 knockdown reduced tumourspheres. Endocrine-resistant models of luminal B breast cancer induced p-PR in 3D cultures and required PR and IRS-1 for tumoursphere formation. Phospho-PR-B cooperates with IRS-1 to promote outgrowth of endocrine-resistant and stem-like breast cancer cells. Targeting phospho-PR/IRS-1 crosstalk may block the emergence of endocrine resistance.
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影响因子：
7.4
作者：
Fillmore, Christine M.;Kuperwasser, Charlotte
通讯作者：
Kuperwasser, Charlotte
影响因子：
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作者：
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通讯作者：
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
8
作者：
Jackson, JG;Zhang, XH;Yee, D
通讯作者：
Yee, D
影响因子：
64.8
作者：
Hosseini H;Obradović MMS;Hoffmann M;Harper KL;Sosa MS;Werner-Klein M;Nanduri LK;Werno C;Ehrl C;Maneck M;Patwary N;Haunschild G;Gužvić M;Reimelt C;Grauvogl M;Eichner N;Weber F;Hartkopf AD;Taran FA;Brucker SY;Fehm T;Rack B;Buchholz S;Spang R;Meister G;Aguirre-Ghiso JA;Klein CA
通讯作者：
Klein CA