Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
Womens Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
Nat Commun. 2022 Apr 19;13(1):2011. doi: 10.1038/s41467-022-29498-9.
Estrogen receptor alpha (ER/ESR1) is frequently mutated in endocrine resistant ER-positive (ER+) breast cancer and linked to ligand-independent growth and metastasis. Despite the distinct clinical features of ESR1 mutations, their role in intrinsic subtype switching remains largely unknown. Here we find that ESR1 mutant cells and clinical samples show a significant enrichment of basal subtype markers, and six basal cytokeratins (BCKs) are the most enriched genes. Induction of BCKs is independent of ER binding and instead associated with chromatin reprogramming centered around a progesterone receptor-orchestrated insulated neighborhood. BCK-high ER+ primary breast tumors exhibit a number of enriched immune pathways, shared with ESR1 mutant tumors. S100A8 and S100A9 are among the most induced immune mediators and involve in tumor-stroma paracrine crosstalk inferred by single-cell RNA-seq from metastatic tumors. Collectively, these observations demonstrate that ESR1 mutant tumors gain basal features associated with increased immune activation, encouraging additional studies of immune therapeutic vulnerabilities.
雌激素受体 alpha（ER/ESR1）在内分泌耐药 ER 阳性（ER+）乳腺癌中经常发生突变，与配体非依赖性生长和转移有关。尽管 ESR1 突变具有明显的临床特征，但它们在内在亚型转换中的作用在很大程度上仍不清楚。在这里，我们发现 ESR1 突变细胞和临床样本显示出基底亚型标志物的显著富集，并且六种基底细胞角蛋白（BCKs）是最富集的基因。BCKs 的诱导不依赖于 ER 结合，而是与围绕孕激素受体协调的隔离邻域的染色质重编程有关。BCK-高的 ER+原发性乳腺癌表现出许多富集的免疫途径，与 ESR1 突变肿瘤共享。S100A8 和 S100A9 是诱导最多的免疫介质之一，涉及通过转移性肿瘤的单细胞 RNA-seq 推断的肿瘤-基质旁分泌串扰。总之，这些观察结果表明，ESR1 突变肿瘤获得了与免疫激活增加相关的基底特征，鼓励对免疫治疗脆弱性进行更多研究。
