Nandy Sushmita Bose, Orozco Alexis, Lopez-Valdez Rebecca, Roberts Rene, Subramani Ramadevi, Arumugam Arunkumar, Dwivedi Alok Kumar, Stewart Viktoria, Prabhakar Gautham, Jones Stephanie, Lakshmanaswamy Rajkumar
Department of Biomedical Sciences, Center of Emphasis in Cancer Research, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA.
Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA.
Br J Cancer. 2017 Nov 21;117(11):1665-1675. doi: 10.1038/bjc.2017.335. Epub 2017 Oct 12.
Meta-analysis shows that women with diabetes have a 20% increased risk of breast cancer and also an increased risk for distant metastasis and mortality. The molecular mechanisms for distant metastasis and mortality in breast cancer patients with diabetes are not very well understood.
We compared the effect of physiological (5 mM) and diabetic (10 mM) levels of glucose on malignant breast epithelial cell invasion and stemness capabilities. We performed microRNA array to determine the dysregulated microRNAs in hyperglycaemic conditions and performed functional and molecular analysis of the gene targets.
Hyperglycaemia leads to hyperactivation of cancer stem cell pool and enhances invasive ability of breast cancer cells. MiR-424 seems to be a key regulator of cancer cell stemness and invasion. Knockdown of miR-424 in cancer cells under euglycaemic conditions leads to enhanced invasion and stem cell activity, whereas ectopic expression of miR-424 in cancer cells under hyperglycaemic conditions results in suppressed invasion and stem cell activity. Cdc42, a target of miR-424, influences cancer stem cell activity by positively regulating prdm14 through activation of pak1 (p-21-activated kinase 1) and stat5.
Our findings establish miR-424→︀cdc42→︀prdm14 axis as a key molecular signalling cascade that might influence breast cancer progression in diabetic patients through hyperactivation of cancer stem cells.
荟萃分析表明，糖尿病女性患乳腺癌的风险增加20%，远处转移和死亡风险也增加。糖尿病乳腺癌患者远处转移和死亡的分子机制尚不完全清楚。
我们比较了生理水平（5 mM）和糖尿病水平（10 mM）的葡萄糖对恶性乳腺上皮细胞侵袭和干性能力的影响。我们进行了 microRNA 芯片分析以确定高血糖条件下失调的 microRNA，并对基因靶点进行了功能和分子分析。
高血糖导致癌症干细胞池过度激活，并增强乳腺癌细胞的侵袭能力。MiR-424似乎是癌细胞干性和侵袭的关键调节因子。在正常血糖条件下敲低癌细胞中的MiR-424会导致侵袭和干细胞活性增强，而在高血糖条件下癌细胞中MiR-424的异位表达会导致侵袭和干细胞活性受到抑制。Cdc42是MiR-424的一个靶点，它通过激活pak1（p-21激活激酶1）和stat5来正向调节prdm14，从而影响癌症干细胞活性。
我们的研究结果确立了MiR-424→︀Cdc42→︀prdm14轴作为一个关键的分子信号级联，它可能通过癌症干细胞的过度激活影响糖尿病患者的乳腺癌进展。
