Breast cancer is the most common cancer in women worldwide, and advanced breast cancer is the leading cause of cancer death in women. In present study, we aim to investigate that role of T-cell lymphoma invasion and metastasis-inducing protein1 (TIAM1) on NVP-BEZ235 resistance to breast cancer MCF7 and MDA-MB-361 cells. Briefly, MCF7 and MDA-MB-361 cells were treated with NVP-BEZ235 and the relative expressions of TIAM1 at both mRNA level and protein level were determined by RT-PCR and western blot. In addition, MCF7 and MDA-MB-361 cells were transfected with TIAM1 knockdown or overexpression vector. Then the IC50 of NVP-BEZ235 on MCF7 and MDA-MB-361 cells were detected by MTT assay. Finally, FGFR/STAT3 pathway protein members were investigated by western blot. Consequently, we found that the mRNA and protein expressions of TIAM1 and FGFR1/3 were dramatically upregulated in NVP-BEZ235-treated group in both MCF7 and MDA-MB-361 cells. Interestingly, TIAM1 knockdown via shRNA decreased the IC50 of NVP-BEZ235 of breast cancer cells, while TIAM1 overexpression increased the IC50 of NVP-BEZ235 of breast cancer cells, which suggested that TIAM1 was one of the contributors for NVP-BEZ235 resistance. In addition, FGFR members including FGFR1/3 showed similar results to TIAM1. Importantly, FGFR inhibitor AZD4547 decreased the IC50 of NVP-BEZ235, which suggested that FGFR downregulation reduced the NVP-BEZ235 resistance to breast cancer cells. In summary, our present study revealed that TIAM1 conferred NVP-BEZ235 resistance to breast cancer cells via activating FGFR/STAT3 pathway.

乳腺癌是全世界女性中最常见的癌症，晚期乳腺癌是女性癌症死亡的主要原因。在本研究中，我们旨在研究T细胞淋巴瘤侵袭和转移诱导蛋白1（TIAM1）在NVP-BEZ235对乳腺癌MCF7和MDA-MB-361细胞的耐药性中的作用。简而言之，用NVP-BEZ235处理MCF7和MDA-MB-361细胞，并通过RT-PCR和蛋白质印迹法测定TIAM1在mRNA水平和蛋白水平上的相对表达。此外，用TIAM1敲低或过表达载体转染MCF7和MDA-MB-361细胞。然后通过MTT法检测NVP-BEZ235对MCF7和MDA-MB-361细胞的IC50。最后，通过蛋白质印迹研究了FGFR / STAT3途径蛋白成员。所以，我们发现，在NVP-BEZ235治疗组的MCF7和MDA-MB-361细胞中，TIAM1和FGFR1 / 3的mRNA和蛋白表达均显着上调。有趣的是，通过shRNA敲低TIAM1会降低乳腺癌细胞NVP-BEZ235的IC50，而TIAM1过表达会提高乳腺癌细胞NVP-BEZ235的IC50，这表明TIAM1是导致NVP-BEZ235耐药的因素之一。此外，包括FGFR1 / 3在内的FGFR成员显示出与TIAM1类似的结果。重要的是，FGFR抑制剂AZD4547降低了NVP-BEZ235的IC50，这表明FGFR下调降低了NVP-BEZ235对乳腺癌细胞的耐药性。总之，我们目前的研究表明TIAM1通过激活FGFR / STAT3途径赋予NVP-BEZ235对乳腺癌细胞的抗性。