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
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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

    0

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    2020-11-14 医路前行4231

    已读

    0

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