预防遗传性乳腺癌或将不用切除也可实现

　　2016年6月20日，英国《自然·医学》在线发表澳大利亚沃尔特与沃尔特伊丽莎·霍尔医学研究所、墨尔本大学、皇家墨尔本医院、皇家女子医院、维多利亚综合癌症中心、美国安进公司的突破性研究成果，发现治疗骨质疏松的药物地诺单抗能够延缓乳腺癌生长。进一步的临床研究将确定其能否作为乳腺癌高风险女性的治疗药物，地诺单抗或将成为乳腺癌易感基因（BRCA）突变携带女性的预防性治疗药物。

　　在健康状态下BRCA1和BRCA2基因能够产生肿瘤抑制性蛋白，帮助修复损伤DNA确保细胞内遗传物质的稳定。但是如果这些基因发生突变或功能紊乱，就会产生错误蛋白无法正常修复DNA损伤，进而增加乳腺癌和卵巢癌的风险，大约有一半携带BRCA1或BRCA2突变基因的女性到70岁时会患上乳腺癌。携带有BRCA1基因突变的女性有着很高的健康风险，因为该突变可显著提高罹患强侵袭性乳腺癌和卵巢癌的几率。目前，很多这样的女性都会选择通过手术来摘除乳房和卵巢组织，以从根本上杜绝癌症的发生。著名女演员安吉丽娜·朱莉曾检出携带该基因突变，据估计这会导致她患乳腺癌的风险增加87%，患卵巢癌的风险增加50%，因此她进行了双侧乳腺切除手术。如果能够在不进行切除手术的情况下，就能在这些高危女性中防止癌症的发生，这无疑将给她们的生活质量带来显著的改善。

　　该研究发现骨质疏松治疗药物地诺单抗能够将上述基因突变危害降低到很低水平。该研究首先对携带BRCA1突变携带者捐献的乳腺组织进行分析，精准地发现一组生长速度很快的细胞，似乎是那些将来可能会癌变形成乳腺癌的祖细胞。这些肿瘤前体细胞与真正的浸润性乳腺癌细胞有许多相似之处，能够快速增殖，对DNA损伤特别敏感，并且很容易积累DNA损伤，这些特点使它们很容易癌变。这些肿瘤前体细胞中都表达着一种名为RANK配体（RANKL）的蛋白分子，能够在女性怀孕和月经期间向乳腺细胞传递生长信号，如果该分子功能发生紊乱，乳腺细胞就会开始分裂并逐渐出现增殖失控导致乳腺癌发生。

　　这一发现是一个重要的突破，因为抑制RANKL蛋白信号通路的药物已经在临床上使用，如地诺单抗，已被批准用于治疗骨质疏松和不可切除的骨巨细胞瘤。之前研究已经证明地诺单抗本身能够靶向RANK配体治疗骨质疏松或治疗发生乳腺癌骨转移的患者。该研究在乳腺癌小鼠模型和分离的人类乳腺癌细胞中检测了RANKL抑制剂地诺单抗对携带BRCA1基因突变的乳房组织肿瘤前体细胞的作用，发现抑制RANKL信号通路能够关闭携带BRCA1基因突变的乳房组织中肿瘤前体细胞的增生，预防或延缓肿瘤发育。这表明可能发现了一种帮助癌症高风险女性，特别是BRCA1突变携带者预防乳腺癌发生的潜在治疗方法，这一策略能够推迟或者防止BRCA1基因突变的携带者罹患乳腺癌。

　　但是，研究者仍然对这些结果保持谨慎态度，希望能够将这些研究结果转化到临床应用，而不仅仅是在小鼠模型和体外细胞模型上得到应用。目前临床研究已经展开，预期进行两年。

Nat Med. 2016 Jun 20. [Epub ahead of print]

RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers.

Nolan E, Vaillant F, Branstetter D, Pal B, Giner G, Whitehead L, Lok SW, Mann GB; Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), Rohrbach K, Huang LY, Soriano R, Smyth GK, Dougall WC, Visvader JE, Lindeman GJ.

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; University of Melbourne, Parkville, Victoria, Australia; Amgen Inc., Seattle, Washington, USA; Royal Melbourne Hospital, Parkville, Victoria, Australia; Royal Women's Hospital, Parkville, Victoria, Australia; Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia.

Individuals who have mutations in the breast-cancer-susceptibility gene BRCA1 (hereafter referred to as BRCA1-mutation carriers) frequently undergo prophylactic mastectomy to minimize their risk of breast cancer. The identification of an effective prevention therapy therefore remains a 'holy grail' for the field. Precancerous BRCA1mut/+ tissue harbors an aberrant population of luminal progenitor cells, and deregulated progesterone signaling has been implicated in BRCA1-associated oncogenesis. Coupled with the findings that tumor necrosis factor superfamily member 11 (TNFSF11; also known as RANKL) is a key paracrine effector of progesterone signaling and that RANKL and its receptor TNFRSF11A (also known as RANK) contribute to mammary tumorigenesis, we investigated a role for this pathway in the pre-neoplastic phase of BRCA1-mutation carriers. We identified two subsets of luminal progenitors (RANK+ and RANK-) in histologically normal tissue of BRCA1-mutation carriers and showed that RANK+ cells are highly proliferative, have grossly aberrant DNA repair and bear a molecular signature similar to that of basal-like breast cancer. These data suggest that RANK+ and not RANK- progenitors are a key target population in these women. Inhibition of RANKL signaling by treatment with denosumab in three-dimensional breast organoids derived from pre-neoplastic BRCA1mut/+ tissue attenuated progesterone-induced proliferation. Notably, proliferation was markedly reduced in breast biopsies from BRCA1-mutation carriers who were treated with denosumab. Furthermore, inhibition of RANKL in a Brca1-deficient mouse model substantially curtailed mammary tumorigenesis. Taken together, these findings identify a targetable pathway in a putative cell-of-origin population in BRCA1-mutation carriers and implicate RANKL blockade as a promising strategy in the prevention of breast cancer.

PMID: 27322743

DOI: 10.1038/nm.4118