Liu Xuemei, Zhao Ling, Derose Yoko S, Lin Yi-Chun, Bieniasz Magdalena, Eyob Henok, Buys Saundra S, Neumayer Leigh, Welm Alana L
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Genes Cancer. 2011 Jul;2(7):753-62. doi: 10.1177/1947601911421924.
Receptor tyrosine kinases (RTKs) have been the subject of intense investigation due to their widespread deregulation in cancer and the prospect of developing targeted therapeutics against these proteins. The Ron RTK has been implicated in tumor aggressiveness and is a developing target for therapy, but its function in tumor progression and metastasis is not fully understood. We examined Ron activity in human breast cancers and found striking predominance of an activated Ron isoform known as short-form Ron (sfRon), whose function in breast tumors has not been explored. We found that sfRon plays a significant role in aggressiveness of breast cancer in vitro and in vivo. sfRon expression was sufficient to convert slow-growing, nonmetastatic tumors into rapidly growing tumors that spontaneously metastasized to liver and bones. Mechanistic studies revealed that sfRon promotes epithelial-mesenchymal transition, invasion, tumor growth, and metastasis through interaction with p85, the regulatory subunit of phosphoinositide 3-kinase (PI3K). Inhibition of PI3K activity, or introduction of a single mutation in the p85 docking site on sfRon, completely eliminated the ability of sfRon to promote tumor growth, invasion, and metastasis. These findings reveal sfRon as an important new player in breast cancer and validate Ron and PI3K as therapeutic targets in this disease.
受体酪氨酸激酶（RTKs）因其在癌症中广泛的失调以及开发针对这些蛋白的靶向治疗药物的前景，一直是深入研究的对象。Ron受体酪氨酸激酶与肿瘤侵袭性有关，是一种正在开发的治疗靶点，但其在肿瘤进展和转移中的功能尚未完全了解。我们检测了人乳腺癌中Ron的活性，发现一种被称为短型Ron（sfRon）的激活型Ron异构体占主导地位，其在乳腺肿瘤中的功能尚未被探索。我们发现sfRon在体外和体内的乳腺癌侵袭性中发挥着重要作用。sfRon的表达足以将生长缓慢、无转移能力的肿瘤转变为快速生长且能自发转移至肝脏和骨骼的肿瘤。机制研究表明，sfRon通过与磷酸肌醇3激酶（PI3K）的调节亚基p85相互作用，促进上皮-间质转化、侵袭、肿瘤生长和转移。抑制PI3K活性，或在sfRon的p85对接位点引入单个突变，可完全消除sfRon促进肿瘤生长、侵袭和转移的能力。这些发现揭示了sfRon是乳腺癌中的一个重要新因子，并验证了Ron和PI3K作为该疾病治疗靶点的有效性。
