Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
Nat Commun. 2020 Oct 30;11(1):5488. doi: 10.1038/s41467-020-19291-x.
The 17q23 amplicon is associated with poor outcome in ER breast cancers, but the causal genes to endocrine resistance in this amplicon are unclear. Here, we interrogate transcriptome data from primary breast tumors and find that among genes in 17q23, PRR11 is a key gene associated with a poor response to therapeutic estrogen suppression. PRR11 promotes estrogen-independent proliferation and confers endocrine resistance in ER breast cancers. Mechanistically, the proline-rich motif-mediated interaction of PRR11 with the p85α regulatory subunit of PI3K suppresses p85 homodimerization, thus enhancing insulin-stimulated binding of p110-p85α heterodimers to IRS1 and activation of PI3K. PRR11-amplified breast cancer cells rely on PIK3CA and are highly sensitive to PI3K inhibitors, suggesting that PRR11 amplification confers PI3K dependence. Finally, genetic and pharmacological inhibition of PI3K suppresses PRR11-mediated, estrogen-independent growth. These data suggest ER/PRR11-amplified breast cancers as a novel subgroup of tumors that may benefit from treatment with PI3K inhibitors and antiestrogens.
17q23 扩增与 ER 阳性乳腺癌不良预后相关，但该扩增中导致内分泌抵抗的因果基因尚不清楚。在这里，我们对原发性乳腺癌肿瘤的转录组数据进行了研究，发现 17q23 中的基因中，PRR11 是与对治疗性雌激素抑制反应不良相关的关键基因。PRR11 促进雌激素非依赖性增殖，并赋予 ER 阳性乳腺癌内分泌抵抗性。在机制上，PRR11 与 PI3K 的 p85α 调节亚基的富含脯氨酸基序介导的相互作用抑制 p85 同源二聚体，从而增强胰岛素刺激的 p110-p85α 异源二聚体与 IRS1 的结合和 PI3K 的激活。PRR11 扩增的乳腺癌细胞依赖于 PIK3CA ，并且对 PI3K 抑制剂高度敏感，这表明 PRR11 扩增赋予了对 PI3K 的依赖性。最后，PI3K 的遗传和药理学抑制抑制了 PRR11 介导的雌激素非依赖性生长。这些数据表明，ER/PRR11 扩增的乳腺癌可能是一种新型肿瘤亚群，可能受益于 PI3K 抑制剂和抗雌激素的治疗。
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