转录调节因子TBX3促进乳腺癌从非侵袭性向侵袭性进展。
The transcriptional regulator TBX3 promotes progression from non-invasive to invasive breast cancer.
作者信息
Krstic Milica, Macmillan Connor D, Leong Hon S, Clifford Allen G, Souter Lesley H, Dales David W, Postenka Carl O, Chambers Ann F, Tuck Alan B
机构信息
Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
The Pamela Greenaway-Kohlmeier Translational Breast Cancer Research Unit, London Regional Cancer Program, London Health Sciences Centre, London, ON, Canada.
出版信息
BMC Cancer. 2016 Aug 23;16(1):671. doi: 10.1186/s12885-016-2697-z.
BACKGROUND
TBX3 is a T-box transcription factor repressor that is elevated in metastatic breast cancer and is believed to promote malignancy of tumor cells, possibly by promoting cell survival and epithelial-mesenchymal transition.
METHODS
The relative expression of TBX3 was assessed in the 21T cell lines which were derived from an individual patient and represent three distinct stages of breast cancer progression: 21PT, atypical ductal hyperplasia; 21NT, ductal carcinoma in situ; and 21MT-1, invasive mammary carcinoma. Two different isoforms of TBX3 (TBX3iso1 and TBX3iso2) were overexpressed to evaluate cell survival/colony forming ability, growth, and invasion in the ductal carcinoma in situ-like 21NT cell line using an in vitro Matrigel model of cancer progression. In addition, TBX3 expression was knocked down to evaluate the effects of downregulating TBX3 on the invasive mammary carcinoma-like 21MT-1 cell line. Finally, PCR array profiling was used to assess alterations in gene expression due to TBX3 overexpression in the 21NT cells.
RESULTS
TBX3 is abundant in the invasive 21MT-1 cell line, while being minimally expressed in the non-invasive 21NT and 21PT cell lines. Overexpression of either TBX3iso1 or TBX3iso2 in 21NT cells resulted in increased cell survival/colony forming ability, growth vs. apoptosis and invasion in Matrigel. In contrast, short hairpin RNA-mediated knockdown of TBX3 in the 21MT-1 cells resulted in smaller colonies, with a more regular, less dispersed (less infiltrative) morphology. Array profiling of the 21NT TBX3 iso1 and iso2 transfectants showed that there are common alterations in expression of several genes involved in signal transduction, cell cycle control/cell survival, epithelial-mesenchymal transition and invasiveness.
CONCLUSIONS
Overall, these results indicate that TBX3 (isoform 1 or 2) expression can promote progression in a model of early breast cancer by altering cell properties involved in cell survival/colony formation and invasiveness, as well as key regulatory and EMT/invasiveness-related gene expressions.
背景
TBX3是一种T-box转录因子抑制因子，在转移性乳腺癌中表达升高，据信它可能通过促进细胞存活和上皮-间质转化来促进肿瘤细胞的恶性发展。
方法
在源自一名个体患者且代表乳腺癌进展三个不同阶段的21T细胞系中评估TBX3的相对表达：21PT，非典型导管增生；21NT，原位导管癌；以及21MT-1，浸润性乳腺癌。使用癌症进展的体外基质胶模型，在原位导管癌样的21NT细胞系中过表达两种不同的TBX3亚型（TBX3iso1和TBX3iso2），以评估细胞存活/集落形成能力、生长和侵袭情况。此外，敲低TBX3表达以评估下调TBX3对浸润性乳腺癌样的21MT-1细胞系的影响。最后，使用PCR阵列分析评估21NT细胞中因TBX3过表达导致的基因表达变化。
结果
TBX3在浸润性的21MT-1细胞系中含量丰富，而在非浸润性的21NT和21PT细胞系中表达极低。在21NT细胞中过表达TBX3iso1或TBX3iso2会导致细胞存活/集落形成能力增强、生长相对于凋亡增加以及在基质胶中的侵袭能力增强。相反，在21MT-1细胞中通过短发夹RNA介导敲低TBX3会导致集落更小，形态更规则、分散性更低（浸润性更低）。对21NT TBX3 iso1和iso2转染细胞的阵列分析表明，参与信号转导、细胞周期控制/细胞存活、上皮-间质转化和侵袭性的几个基因的表达存在共同变化。
结论
总体而言，这些结果表明TBX3（亚型1或2）的表达可通过改变参与细胞存活/集落形成和侵袭性的细胞特性以及关键调节和EMT/侵袭性相关基因的表达，促进早期乳腺癌模型的进展。
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