Gomes Inês, de Almeida Bernardo P, Dâmaso Sara, Mansinho André, Correia Inês, Henriques Sara, Cruz-Duarte Raquel, Vilhais Guilherme, Félix Pedro, Alves Patrícia, Corredeira Patrícia, Barbosa-Morais Nuno L, Costa Luis, Casimiro Sandra
Luis Costa Laboratory, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
Nuno Morais Laboratory, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
Oncotarget. 2020 May 12;11(19):1714-1728. doi: 10.18632/oncotarget.27576.
The role of RANKL-RANK pathway in progesterone-driven mammary carcinogenesis and triple negative breast cancer tumorigenesis has been well characterized. However, and despite evidences of the existence of RANK-positive hormone receptor (HR)-positive breast tumors, the implication of RANK expression in HR-positive breast cancers has not been addressed before. Here, we report that RANK pathway affects the expression of cell cycle regulators and decreases sensitivity to fulvestrant of estrogen receptor (ER)-positive (ER+)/HER2- breast cancer cells, MCF-7 and T47D. Moreover, RANK overexpressing cells had a staminal and mesenchymal phenotype, with decreased proliferation rate and decreased susceptibility to chemotherapy, but were more invasive . analysis of the transcriptome of human breast tumors, confirmed the association between expression and stem cell and mesenchymal markers in ER+HER2- tumors. Importantly, exposure of ER+HER2- cells to continuous RANK pathway activation by exogenous RANKL, and , induced a negative feedback effect, independent of RANK levels, leading to the downregulation of HR and increased resistance to hormone therapy. These results suggest that ER+HER2- RANK-positive cells may constitute an important reservoir of slow cycling, therapy-resistance cancer cells; and that RANK pathway activation is deleterious in all ER+HER2- breast cancer cells, independently of RANK levels.
RANKL-RANK通路在孕激素驱动的乳腺癌发生及三阴性乳腺癌肿瘤发生中的作用已得到充分阐明。然而，尽管有证据表明存在RANK阳性激素受体（HR）阳性的乳腺肿瘤，但RANK表达在HR阳性乳腺癌中的意义此前尚未得到探讨。在此，我们报告RANK通路影响细胞周期调节因子的表达，并降低雌激素受体（ER）阳性（ER+）/HER2阴性乳腺癌细胞MCF-7和T47D对氟维司群的敏感性。此外，过表达RANK的细胞具有干性和间充质表型，增殖率降低且对化疗的敏感性降低，但侵袭性更强。对人类乳腺肿瘤转录组的分析证实了ER+HER2-肿瘤中RANK表达与干细胞及间充质标志物之间的关联。重要的是，通过外源性RANKL使ER+HER2-细胞持续暴露于RANK通路激活状态，以及，诱导了一种负反馈效应，该效应独立于RANK水平，导致HR下调并增加对激素治疗的耐药性。这些结果表明，ER+HER2-RANK阳性细胞可能构成缓慢循环、耐药癌细胞的重要储存库；并且RANK通路激活对所有ER+HER2-乳腺癌细胞都是有害的，与RANK水平无关。
