Division of Medical Oncology, Department of Medicine, CU Anschutz Medical Campus, Aurora, CO, 80045, USA.
Young Women's BC Translational Program, CU Anschutz Medical Campus, Aurora, CO, 80045, USA.
Oncogene. 2020 Mar;39(13):2772-2785. doi: 10.1038/s41388-020-1192-9. Epub 2020 Feb 4.
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.
年轻女性被诊断患有乳腺癌（BC），由于转移率增加，预后较差。此外，最近一次分娩后 10 年内被诊断患有 BC 的女性比年龄和分期相匹配的未生育女性发生转移的可能性大约高出三倍。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特性驱动肿瘤进展。我们发表的结果表明 SEMA7A 在乳腺癌细胞生长、运动性、侵袭和肿瘤相关淋巴管生成中发挥作用，所有这些在 PPBC 的临床前模型中也都增加了。然而，SEMA7A 是否在 PPBC 中驱动进展在很大程度上仍未得到探索。本文呈现的结果表明，沉默 SEMA7A 可减少 PPBC 模型中的肿瘤生长，而过表达 SEMA7A 足以增加未生育宿主中的生长。此外，我们表明 SEMA7A 促进了 PPBC 进展的多个已知驱动因素，包括肿瘤相关 COX-2 表达和肿瘤微环境中纤维母细胞介导的胶原蛋白沉积。此外，我们首次表明表达 SEMA7A 的细胞沉积纤维连接蛋白以促进肿瘤细胞存活。最后，我们表明 SEMA7A/COX-2/FN 的共表达可预测乳腺癌患者队列的不良预后。这些研究表明 SEMA7A 是 BC 进展的关键介质，靶向 SEMA7A 可能为新的治疗策略开辟途径。
