Br J Cancer：IRS-1介导ER+乳腺癌中PR驱动的干细胞性和内分泌抗性

2020-11-14 xiaozeng MedSci原创

乳腺癌作为女性中最常见的恶性肿瘤，在大多数的患者中（约75％）均检测到雌激素受体（ER）和孕激素受体（PR）的表达。靶向ER的疗法是目前该疾病的一种主要治疗手段，然而耐药性的产生在患者中特别普遍。当前

乳腺癌作为女性中最常见的恶性肿瘤，在大多数的患者中（约75％）均检测到雌激素受体（ER）和孕激素受体（PR）的表达。靶向ER的疗法是目前该疾病的一种主要治疗手段，然而耐药性的产生在患者中特别普遍。当前对于晚期ER+乳腺癌患者主要采用内分泌治疗和抑制CDK4/6的联合治疗策略，该策略可显著改善患者的无进展生存期和总体生存期。

PR在临床上常用作检测ER转录活性的一个生物标记。虽然多项研究表明激活的PR可以拮抗ER，而最新的研究发现，在晚期ER+乳腺癌中，PR能够作为肿瘤发生发展相关的驱动因子行使独特作用。PR作为内分泌反应的有效调节因子，在异常信号转导状态的癌症中，PR的磷酸化会显著改变类固醇激素受体的作用。

该研究通过单细胞RNAseq技术，对携带ER+乳腺癌患者移植瘤（PDXs）小鼠中原发瘤和转移瘤进行转录组学分析，并通过体外实验研究相关内分泌抗性和干细胞特性的相关机制。

示意图

研究人员发现，PR第294位Ser丝氨酸磷酸化（p-PR）对应着ER+乳腺癌患者的不良预后。相对于原发性的PDX肿瘤，转移瘤中具有丰富的p-PR，表现出激活的PR状态，并伴随着PGR和IRS-1的表达水平升高。而在PR激活的乳腺癌模型中缺少IGF1R的表达，并出现了获得性胰岛素超敏反应以及对他莫昔芬（tamoxifen）不敏感。

激活的p-PR+乳腺癌细胞中ALDH+和CD24-/CD44的表达升高并能够形成更大的肿瘤球。E2可诱导PR/IRS-1的相互作用且在含p-PR的转录复合物中将IGF-1Rβ交换为IRS-1。抑制IRS-1或IR以及敲低IRS-1均可减小肿瘤球的形成。研究人员进一步发现，三维培养的管腔B型乳腺癌内分泌抗性模型能够诱导p-PR磷酸化产生，且肿瘤球的形成需要PR和IRS-1的表达。

p-PR在PDXs中富集

综上，磷酸化的PR/B与IRS-1能够协同促进内分泌抗性和干细胞样乳腺癌细胞的生长。而靶向p-PR/IRS-1或可预防患者中内分泌抗性的出现。

原始出处：

Dwyer, A.R., Truong, T.H., Kerkvliet, C.P. et al. Insulin receptor substrate-1 (IRS-1) mediates progesterone receptor-driven stemness and endocrine resistance in oestrogen receptor+ breast cancer. Br J Cancer (04 November 2020).

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2021-03-29 yige2012

#抗性#

112 0
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2021-06-11 lqrandywkz

#细胞性#

87 0
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2020-11-17 一叶知秋

#分泌#

74 0
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2020-11-17 独孤立克

干细胞是热点，但是进入临床仍然需要时间和临床疗效验证哦

144 0
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2020-11-15 ms3117646317107274

#S-1#

77 0
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2020-11-14 医路前行4231

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