2篇【Nature子刊】:为预防家族性癌症支招,朱莉也许并不用切除乳房和卵巢
2016/06/23
2010年,奥地利科学家就在《Nature》上证实了性激素能够通过RANKL蛋白及其受体RANK触发乳腺癌的产生。那么,是否可通过这两个分子来实现对乳腺癌的预防?近日,《Nature Medicine》及《Cell Research》上的两项研究回答了这个问题,为乳腺癌的预防带来了曙光。


众所周知,携带BRCA1基因突变的个体患侵袭性乳腺癌的风险更高,因而BRCA1突变携带者通常会选择乳腺和卵巢切除手术,以降低乳腺癌和卵巢癌的风险。美国好莱坞女星安吉丽娜•朱莉因带有遗传性BRCA1基因,由于乳腺癌罹患风险增至87%,她于2013年5月选择了双乳切除术;此外,BRCA1基因使朱莉患卵巢癌的风险为50%,由于担心罹患卵巢癌,2015年3月,她又选择切除了卵巢和输卵管。从此,乳腺切除和卵巢切除似乎成为家族性乳腺癌和卵巢癌常规的预防措施,然而手术会给机体带来很大的伤害,它并不是一种完美的预防措施。

2010年,奥地利科学家就在《Nature》上证实了性激素能够通过RANKL蛋白及其受体RANK触发乳腺癌的产生。那么,能否通过这两个分子来实现对乳腺癌的预防?近日,《Nature Medicine》及《Cell Research》上的两项研究回答了这个问题,为乳腺癌的预防带来了曙光。

《Nature Medicine》:抑基因突变新药 有助女性预防乳腺癌


澳大利亚的研究人员发现,现有药物对BRCA1基因相关乳腺癌的预防具有很大的潜质。相关结论于6月20日发表在《Nature Medicine》杂志上。

在该研究中,研究人员利用BRCA1基因缺陷携带者捐赠的乳腺组织,精准定位导致乳腺癌风险增高的细胞,结果发现狄诺塞麦(Denosumab)药物对乳腺癌的预防具有很大的潜质,如果通过临床研究证实,这将为遗传风险高的女性提供非手术策略来预防乳腺癌。

研究发现,BRCA1基因突变携带者乳腺组织中的癌症前体细胞与侵袭性乳腺癌有许多相似之处,这些细胞迅速增殖,并更容易损害其DNA,从而更容易导致癌症的发生。但令人兴奋的是,这些癌前病变细胞可以通过一种RANK标记蛋白来识别。

研究人员表示,“研究发现RANK可作为癌前病变的标志物,这是个重要的突破,因为RANK信号通路抑制剂已在临床中使用,其中一种抑制剂——狄诺塞麦(Denosumab)已在临床中用于治疗骨质酥松症和扩散至骨骼的乳腺癌,因此我们调查了RANK抑制剂对BRCA1突变者乳腺组织中癌症前体细胞的影响。”

研究小组发现,在实验室模型中,RANK抑制剂可关闭BRCA1基因缺陷携带者乳腺组织中细胞的生长,并抑制乳腺癌的发展。“我们认为这种方法可延缓或阻止家族性BRCA1突变乳腺癌的发展,目前已开展临床试验进一步调查。该研究对BRCA1基因缺陷携带者来说具有重要的意义,或许将来她们再也不用通过乳房或卵巢切除来预防癌症”,研究人员表示。为了推进这项工作,必须在临床试验中正式检测denosumab药物对乳腺癌发展的影响,因为目前该药物未被批准用于乳腺癌的预防。

本研究作者Visvader教授说,“该研究以十多年乳腺干细胞的研究为基础,通过深入剖析正常乳腺组织的发展,我们确定了癌症形成的罪魁祸首,令人兴奋的是,该研究可能是预防遗传高风险乳腺癌的‘圣杯’。”

《Cell Research》:预防乳腺癌有戏

以往研究已证实RANKL是BRCA1突变驱动的乳腺癌的主要驱动因子,5月31日,奥地利等国家的研究人员在《Cell Research》上揭示在BRCA1突变小鼠体内阻断RANKL/RANK系统可使乳腺大体上正常发展,然而在对照小鼠体内,侵袭性乳腺癌更容易生长。

为了确定人类身上是否也会出现类似的效果,研究人员将BRCA突变携带者捐赠的乳腺组织进行细胞分离,并置于体外培养。研究人员发现,抑制RANKL蛋白可使这些细胞的生长和扩散能力显著下降。同时研究人员通过23000名女性证实RANK基因突变与BRCA1/2基因突变携带者的乳腺癌风险相关联。

针对此结果,研究人员认为阻断RANKL/RANK的药物对BRCA基因突变携带者的乳腺癌预防具有很大的潜力,并对目前已被批准靶向RANKL的抗体药物——狄诺塞麦(Denosumab)寄予厚望。

所有文章仅代表作者观点,不代表本站立场。如若转载请联系原作者。
查看更多
  • RANKL/RANK control Brca1 mutation-driven mammary tumors

    Breast cancer is the most common female cancer, affecting approximately one in eight women during their life-time. Besides environmental triggers and hormones, inherited mutations in the breast cancer 1 (BRCA1) or BRCA2 genes markedly increase the risk for the development of breast cancer. Here, using two different mouse models, we show that genetic inactivation of the key osteoclast differentiation factor RANK in the mammary epithelium markedly delayed onset, reduced incidence, and attenuated progression of Brca1;p53 mutation-driven mammary cancer. Long-term pharmacological inhibition of the RANK ligand RANKL in mice abolished the occurrence of Brca1 mutation-driven pre-neoplastic lesions. Mechanistically, genetic inactivation of Rank or RANKL/RANK blockade impaired proliferation and expansion of both murine Brca1;p53 mutant mammary stem cells and mammary progenitors from human BRCA1 mutation carriers. In addition, genome variations within the RANK locus were significantly associated with risk of developing breast cancer in women with BRCA1 mutations. Thus, RANKL/RANK control progenitor cell expansion and tumorigenesis in inherited breast cancer. These results present a viable strategy for the possible prevention of breast cancer in BRCA1 mutant patients.

    展开 收起
  • RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers

    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 cells1, and deregulated progesterone signaling has been implicated in BRCA1-associated oncogenesis2, 3, 4, 5. Coupled with the findings that tumor necrosis factor superfamily member 11 (TNFSF11; also known as RANKL) is a key paracrine effector of progesterone signaling6, 7, 8, 9, 10 and that RANKL and its receptor TNFRSF11A (also known as RANK) contribute to mammary tumorigenesis11, 12, 13, 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.

    展开 收起
发表评论 我在frontend\modules\comment\widgets\views\文件夹下面 test