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众所周知，雌激素可以促进雌激素受体阳性乳腺肿瘤的生长。不过，流行病学研究调查了绝经后女性接受激素补充疗法的乳腺癌预后特征，结果发现肿瘤扩散反而显著减少，表明雌激素可能具有防止癌细胞浸润的作用。 2018年7月30日，英国《自然》旗下《自然·通讯》在线发表亚利桑那大学、哈佛大学达纳法伯癌症研究所、霍华德休斯医学研究所、洛杉矶加利福尼亚大学西奈雪松医疗中心、法国斯特拉斯堡大学的研究报告，发现雌激素可以通过肌动蛋白细胞骨架结构抑制雌激素受体阳性乳腺癌细胞发生浸润。 该研究发现，雌激素主要通过增加ENA/VASP样蛋白（EVL）的转录，从而抑制雌激素受体阳性乳腺癌细胞的浸润。血管舒张剂刺激磷蛋白（VASP）能与肌动蛋白、肌动蛋白抑制蛋白结合的蛋白质，磷酸化可以调节此蛋白质与肌动蛋白的结合，进而促进肌动蛋白的聚合。EVL可以促进抑制细胞运动动力的抑制性皮质肌动蛋白束产生，参与肌动蛋白细胞骨架重组，以及细胞迁移、收缩环形成和细胞间附着，并且对于雌激素受体抑制体外和体内肿瘤细胞浸润至关重要。有趣的是，虽然抗雌激素内分泌疗法具有抑制肿瘤生长的好处，但是可以减少EVL表达并且增加肿瘤的局部浸润。 因此，该研究结果揭示了雌激素对雌激素受体阳性乳腺癌的正反效应：一方面雌激素具有促进雌激素受体阳性乳腺癌生长的明确作用，另一方面雌激素通过肌动蛋白细胞骨架重组，具有抑制雌激素受体阳性乳腺癌浸润的重要作用，为难治型雌激素受体阳性乳腺癌的靶向疗法奠定了基础。 相关阅读 Nat Commun. 2018 Jul 30;9(7):2980. The actin cytoskeletal architecture of estrogen receptor positive breast cancer cells suppresses invasion. Marco Padilla-Rodriguez, Sara S. Parker, Deanna G. Adams, Thomas Westerling, Julieann I. Puleo, Adam W. Watson, Samantha M. Hill, Muhammad Noon, Raphael Gaudin, Jesse Aaron, Daoqin Tong, Denise J. Roe, Beatrice Knudsen, Ghassan Mouneimne. University of Arizona, Tucson, AZ, USA; Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Howard Hughes Medical Institute, Ashburn, VA, USA; Cedars-Sinai Medical Center, Los Angeles, CA, USA. Estrogen promotes growth of estrogen receptor-positive (ER+) breast tumors. However, epidemiological studies examining the prognostic characteristics of breast cancer in postmenopausal women receiving hormone replacement therapy reveal a significant decrease in tumor dissemination, suggesting that estrogen has potential protective effects against cancer cell invasion. Here, we show that estrogen suppresses invasion of ER+ breast cancer cells by increasing transcription of the Ena/VASP protein, EVL, which promotes the generation of suppressive cortical actin bundles that inhibit motility dynamics, and is crucial for the ER-mediated suppression of invasion in vitro and in vivo. Interestingly, despite its benefits in suppressing tumor growth, anti-estrogenic endocrine therapy decreases EVL expression and increases local invasion in patients. Our results highlight the dichotomous effects of estrogen on tumor progression and suggest that, in contrast to its established role in promoting growth of ER+ tumors, estrogen has a significant role in suppressing invasion through actin cytoskeletal remodeling. DOI: 10.1038/s41467-018-05367-2
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