澳大利亚墨尔本大学Jane E. Visvader等研究人员合作发现，异常管腔祖细胞和mTORC1可作为BRCA2基因突变携带者预防乳腺癌的潜在靶点。2024年1月12日，《自然—细胞生物学》杂志在线发表了这项成果。

利用年龄匹配的绝经前女性的肿瘤前标本，研究人员展示了BRCA2^mut/+组织中管腔区的广泛失调，包括异常ERBB3^lo管腔祖细胞和成熟细胞的扩增，以及非典型雌激素受体（ER）阳性病变的存在。转录谱分析和功能测定显示，在BRCA2^mut/+乳腺组织中，ERBB3^lo祖细胞的蛋白稳态和翻译受到干扰，与衰老无关。

带有BRCA2截断突变的肿瘤也存在类似的分子扰动。ERBB3^lo祖细胞可产生ER⁺和ER^-细胞，有可能成为ER阳性或三阴性癌症的原发细胞。在BRCA2缺陷乳腺癌的临床前模型中，使用mTORC1抑制剂进行短期治疗可大大减少肿瘤发生，从而为BRCA2突变携带者发现了一种潜在的预防策略。

据介绍，遗传BRCA2致病变体会给人的一生带来罹患乳腺癌的巨大风险。对于这些经常接受预防性乳房切除术的人来说，确定BRCA2突变乳腺癌的原发细胞和导致转化的靶向干扰仍是一个难题。

附：英文原文

Title: Identification of aberrant luminal progenitors and mTORC1 as a potential breast cancer prevention target in BRCA2 mutation carriers

Author: Joyce, Rachel, Pascual, Rosa, Heitink, Luuk, Capaldo, Bianca D., Vaillant, Franois, Christie, Michael, Tsai, Minhsuang, Surgenor, Elliot, Anttila, Casey J. A., Rajasekhar, Pradeep, Jackling, Felicity C., Trussart, Marie, Milevskiy, Michael J. G., Song, Xiaoyu, Li, Mengbo, Teh, Charis E., Gray, Daniel H. D., Smyth, Gordon K., Chen, Yunshun, Lindeman, Geoffrey J., Visvader, Jane E.

Issue&Volume: 2024-01-12

Abstract: Inheritance of a BRCA2 pathogenic variant conveys a substantial life-time risk of breast cancer. Identification of the cell(s)-of-origin of BRCA2-mutant breast cancer and targetable perturbations that contribute to transformation remains an unmet need for these individuals who frequently undergo prophylactic mastectomy. Using preneoplastic specimens from age-matched, premenopausal females, here we show broad dysregulation across the luminal compartment in BRCA2mut/+ tissue, including expansion of aberrant ERBB3lo luminal progenitor and mature cells, and the presence of atypical oestrogen receptor (ER)-positive lesions. Transcriptional profiling and functional assays revealed perturbed proteostasis and translation in ERBB3lo progenitors in BRCA2mut/+ breast tissue, independent of ageing. Similar molecular perturbations marked tumours bearing BRCA2-truncating mutations. ERBB3lo progenitors could generate both ER+ and ER cells, potentially serving as cells-of-origin for ER-positive or triple-negative cancers. Short-term treatment with an mTORC1 inhibitor substantially curtailed tumorigenesis in a preclinical model of BRCA2-deficient breast cancer, thus uncovering a potential prevention strategy for BRCA2 mutation carriers.

DOI: 10.1038/s41556-023-01315-5

Source: https://www.nature.com/articles/s41556-023-01315-5