Postpartum breast cancer progression is driven by semaphorin 7a-mediated invasion and survival.
Postpartum breast cancer progression is driven by semaphorin 7a-mediated invasion and survival.
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产后乳腺癌的进展是由信号蛋白 7a 介导的侵袭和存活驱动的。
DOI：
10.1038/s41388-020-1192-9
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发表时间：
2020
期刊：
影响因子：
8
通讯作者：
Lyons,TraciR
中科院分区：
文献类型：
--
作者：
Tarullo,SarahE;Hill,RyanC;Hansen,KirkC;Behbod,Fariba;Borges,VirginiaF;Nelson,AndrewC;Lyons,TraciR
诊断为乳腺癌（BC）的年轻女性由于转移率增加而预后不良。此外，最近一次分娩后10年内确诊的妇女发生转移的可能性大约是年龄和分期匹配的未经产妇女的三倍。我们将这些病例定义为产后乳腺癌（PPBC），并提出产后乳腺的独特生物学驱动肿瘤进展。我们发表的结果揭示了SEMA 7A在乳腺肿瘤细胞生长、运动、侵袭和肿瘤相关淋巴管生成中的作用，所有这些在PPBC的临床前模型中也增加。然而，SEMA 7A是否推动PPBC的进展在很大程度上尚未探索。我们在此呈现的结果表明，SEMA 7A的沉默降低了PPBC模型中的肿瘤生长，而过表达足以增加未生育宿主中的生长。此外，我们发现SEMA 7A促进了PPBC进展的多种已知驱动因素，包括肿瘤相关的考克斯-2表达和成纤维细胞介导的胶原蛋白在肿瘤微环境中的沉积。此外，我们首次表明，SEMA 7A表达细胞存款纤连蛋白，以促进肿瘤细胞的生存。最后，我们发现SEMA 7A/考克斯-2/FN的共表达预示着乳腺癌患者队列的不良预后。这些研究表明SEMA 7A是BC进展的关键介质，靶向SEMA 7A可能为新的治疗策略开辟途径。
Young women diagnosed with breast cancer (BC) have poor prognosis due to increased rates of metastasis. In addition, women diagnosed within 10 years of most recent childbirth are approximately three times more likely to develop metastasis than age- and stage-matched nulliparous women. We define these cases as postpartum BC (PPBC) and propose that the unique biology of the postpartum mammary gland drives tumor progression. Our published results revealed roles for SEMA7A in breast tumor cell growth, motility, invasion, and tumor-associated lymphangiogenesis, all of which are also increased in preclinical models of PPBC. However, whether SEMA7A drives progression in PPBC remains largely unexplored. Our results presented herein show that silencing of SEMA7A decreases tumor growth in a model of PPBC, while overexpression is sufficient to increase growth in nulliparous hosts. Further, we show that SEMA7A promotes multiple known drivers of PPBC progression including tumor-associated COX-2 expression and fibroblast-mediated collagen deposition in the tumor microenvironment. In addition, we show for the first time that SEMA7A-expressing cells deposit fibronectin to promote tumor cell survival. Finally, we show that co-expression of SEMA7A/COX-2/FN predicts for poor prognosis in breast cancer patient cohorts. These studies suggest SEMA7A as a key mediator of BC progression, and that targeting SEMA7A may open avenues for novel therapeutic strategies.