Department of Medicine, Cancer Research Program, McGill University Health Centre, McGill University, Montreal, Québec, Canada.
Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates.
Endocr Relat Cancer. 2019 Mar;26(3):321-337. doi: 10.1530/ERC-18-0523.
Triple-negative breast cancer (TNBC) accounts for ~20% of all breast cancer cases. The management of TNBC represents a challenge due to its aggressive phenotype, heterogeneity and lack of targeted therapy. Loss of cell differentiation and enrichment with breast cancer stem-like cells (BCSC) are features of TNBC contributing to its aggressive nature. Here, we found that treatment of TNBC cells with PRL significantly depletes the highly tumorigenic BCSC subpopulations CD44+/CD24- and ALDH+ and differentiates them to the least tumorigenic CD44-/CD24- and ALDH- phenotype with limited tumorsphere formation and self-renewal capacities. Importantly, we found PRL to induce a heterochromatin phenotype marked by histone H3 lysine 9 trimethylation (H3K9me3) and accompanied by ultra-structural cellular architecture associated with differentiation and senescence rendering the cells refractory to growth signals. Crucially, we found PRL to mediate these effects in vivo in a pre-clinical animal xenograft of TNBC controlling tumor growth. These results reveal that the lactogenic hormone PRL may exert its anti-tumorigenic effects on TNBC through cellular reprogramming indicative of differentiation resulting in the depletion of BCSCs and restricting tumorigenesis.
三阴性乳腺癌（TNBC）约占所有乳腺癌病例的 20%。由于其侵袭性表型、异质性和缺乏靶向治疗，TNBC 的治疗极具挑战性。细胞分化的丧失和乳腺癌干细胞样细胞（BCSC）的富集是 TNBC 具有侵袭性的特征，导致其具有侵袭性。在这里，我们发现 PRL 治疗 TNBC 细胞可显著消耗高致瘤性 BCSC 亚群 CD44+/CD24-和 ALDH+，并将其分化为致瘤性最低的 CD44-/CD24-和 ALDH-表型，肿瘤球形成和自我更新能力有限。重要的是，我们发现 PRL 可诱导异染色质表型，其特征是组蛋白 H3 赖氨酸 9 三甲基化（H3K9me3），并伴有与分化和衰老相关的超微结构细胞结构，使细胞对生长信号产生抗性。至关重要的是，我们发现 PRL 在 TNBC 的临床前动物异种移植模型中可介导这些作用，从而控制肿瘤生长。这些结果表明，催乳素等泌乳激素可能通过细胞重编程发挥其对 TNBC 的抗肿瘤作用，从而导致 BCSC 的消耗并限制肿瘤发生。
