Protein kinase D1 regulates matrix metalloproteinase expression and inhibits breast cancer cell invasion.
Protein kinase D1 regulates matrix metalloproteinase expression and inhibits breast cancer cell invasion.
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DOI：
10.1186/bcr2232
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Storz P
中科院分区：
文献类型：
--
作者：
Eiseler T;Döppler H;Yan IK;Goodison S;Storz P
调控乳腺肿瘤细胞侵袭性的生物学和分子事件需要进一步揭示，以开发有效的治疗方法来阻止乳腺癌的扩张和转移。对浸润性乳腺癌和正常乳腺以及乳腺癌细胞株的人体组织样本进行了蛋白激酶D(PKD)的表达评估，以测试表达变化是否可以作为浸润性乳腺癌的标志。我们进一步利用特定的PKD1-shRNA和诱导表达系统来分析PKD1在二维(2D)和三维(3D)培养中对乳腺癌细胞株侵袭行为的作用。乳腺癌细胞系的侵袭行为与基质金属蛋白酶(MMPs)有关，因此我们还确定了PKD1是否调节这些酶的表达和活性。我们发现，丝氨酸/苏氨酸激酶PKD1在正常乳腺组织的导管上皮细胞中高表达，但在所有分析的人类浸润性乳腺肿瘤样本中，其表达降低了95%以上。此外，PKD1在高侵袭性乳腺癌细胞系中不表达，而在非侵袭性或极低侵袭性乳腺癌细胞系中表达。我们的结果进一步表明，在MDA-MB-231细胞中，通过DNA甲基化的表观遗传沉默抑制了PKD1的表达。在2D和3D细胞培养中，在MDA-MB-231细胞中结构性活性PKD1的重新表达显著降低了其侵袭能力。此外，在2D和3D细胞培养中，通过shRNA下调PKD1的表达，MCF-7细胞获得了侵袭能力。PKD1还调节乳腺癌细胞MMPs、MMP2、MMP7、MMP9、MMP10、MMP11、MMP13、MMP14和MMP15的表达，为PKD1介导乳腺癌细胞的侵袭表型提供了可能的机制。我们的结果表明，PKD1的表达降低是浸润性乳腺癌的一个标志。他们进一步表明，PKD1表达的缺失增加了乳腺癌细胞的恶性潜能。这可能是由于PKD1作为基质金属蛋白酶表达的负调控因子所致。我们的数据表明，PKD1的重新表达是一种潜在的治疗策略。
The biological and molecular events that regulate the invasiveness of breast tumour cells need to be further revealed to develop effective therapies that stop breast cancer from expanding and metastasising. Human tissue samples of invasive breast cancer and normal breast, as well as breast cancer cell lines, were evaluated for protein kinase D (PKD) expression, to test if altered expression could serve as a marker for invasive breast cancer. We further utilised specific PKD1-shRNA and a system to inducibly-express PKD1 to analyse the role of PKD1 in the invasive behaviour of breast cancer cell lines in two-dimensional (2D) and three-dimensional (3D) culture. Invasive behaviour in breast cancer cell lines has been linked to matrix metalloproteinases (MMPs), so we also determined if PKD1 regulates the expression and activity of these enzymes. We found that the serine/threonine kinase, PKD1, is highly expressed in ductal epithelial cells of normal human breast tissue, but is reduced in its expression in more than 95% of all analysed samples of human invasive breast tumours. Additionally, PKD1 is not expressed in highly invasive breast cancer cell lines, whereas non-invasive or very low-invasive breast cancer cell lines express PKD1. Our results further implicate that in MDA-MB-231 cells PKD1 expression is blocked by epigenetic silencing via DNA methylation. The re-expression of constitutively-active PKD1 in MDA-MB-231 cells drastically reduced their ability to invade in 2D and 3D cell culture. Moreover, MCF-7 cells acquired the ability to invade in 2D and 3D cell culture when PKD1 expression was knocked-down by shRNA. PKD1 also regulated the expression of breast cancer cell MMPs, MMP-2, MMP-7, MMP-9, MMP-10, MMP-11, MMP-13, MMP-14 and MMP-15, providing a potential mechanism for PKD1 mediation of the invasive phenotype. Our results identify decreased expression of the PKD1 as a marker for invasive breast cancer. They further suggest that the loss of PKD1 expression increases the malignant potential of breast cancer cells. This may be due to the function of PKD1 as a negative regulator of MMP expression. Our data suggest re-expression of PKD1 as a potential therapeutic strategy.
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DOI：
10.1016/s0006-291x(03)01161-6
发表时间：
2003-07-25
影响因子：
3.1
作者：
Jaggi, M;Rao, PS;Balaji, KC
通讯作者：
Balaji, KC
影响因子：
4.8
作者：
Ramos-DeSimone, N;Hahn-Dantona, E;Quigley, JP
通讯作者：
Quigley, JP
影响因子：
8
作者：
Farmer, P;Bonnefoi, H;Iggo, R
通讯作者：
Iggo, R
影响因子：
3.5
作者：
Eiseler, Tim;Schmid, Michael A.;Hausser, Angelika
通讯作者：
Hausser, Angelika
影响因子：
5.6
作者：
Hegedus, Luca;Cho, Hyojin;Eliceiri, George L.
通讯作者：
Eliceiri, George L.