Division of Medical Oncology, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Young Women's Breast Cancer Translational Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Cancer Res. 2021 Jan 1;81(1):187-198. doi: 10.1158/0008-5472.CAN-20-1601. Epub 2020 Oct 29.
Approximately 70% of all breast cancers are estrogen receptor-positive (ER breast cancer), and endocrine therapy has improved survival for patients with ER breast cancer. However, up to half of these tumors recur within 20 years. Recurrent ER breast cancers develop resistance to endocrine therapy; thus, novel targets are needed to treat recurrent ER breast cancer. Here we report that semaphorin 7A (SEMA7A) confers significantly decreased patient survival rates in ER breast cancer. SEMA7A was hormonally regulated in ER breast cancer, but its expression did not uniformly decrease with antiestrogen treatments. Additionally, overexpression of SEMA7A in ER cell lines drove increased growth in the presence of estrogen deprivation, tamoxifen, and fulvestrant. , SEMA7A conferred primary tumor resistance to fulvestrant and induced lung metastases. Prosurvival signaling was identified as a therapeutic vulnerability of ERSEMA7A tumors. We therefore propose that targeting this pathway with inhibitors of survival signaling such as venetoclax may prove efficacious for treating SEMA7A tumors. SIGNIFICANCE: SEMA7A predicts for and likely contributes to poor response to standard-of-care therapies, suggesting that patients with SEMA7AER tumors may benefit from alternative therapeutic strategies. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/1/187/F1.large.jpg.
大约 70%的乳腺癌是雌激素受体阳性（ER 阳性乳腺癌），内分泌治疗改善了 ER 阳性乳腺癌患者的生存。然而，多达一半的肿瘤在 20 年内复发。复发性 ER 阳性乳腺癌对内分泌治疗产生耐药性；因此，需要新的靶点来治疗复发性 ER 阳性乳腺癌。在这里，我们报告 SEMA7A（神经鞘磷脂 7A）可显著降低 ER 阳性乳腺癌患者的生存率。SEMA7A 在 ER 阳性乳腺癌中受激素调节，但随着抗雌激素治疗其表达并未均匀下降。此外，在缺乏雌激素、他莫昔芬和氟维司群的情况下，SEMA7A 在 ER 细胞系中的过表达会导致生长增加。在原发性肿瘤中，SEMA7A 对氟维司群具有耐药性，并诱导肺转移。存活信号被确定为 ERSEMA7A 肿瘤的治疗弱点。因此，我们提出用生存信号抑制剂（如 venetoclax）靶向该途径可能对治疗 SEMA7A 肿瘤有效。意义：SEMA7A 预测并可能导致对标准治疗方法的反应不佳，这表明 SEMA7AER 肿瘤患者可能受益于替代治疗策略。
