Bioinformatics Centre and Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China.
PLoS One. 2013 Jul 18;8(7):e70017. doi: 10.1371/journal.pone.0070017. Print 2013.
Directly comparing gene expression profiles of estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancers cannot determine whether differentially expressed genes between these two subtypes result from dysregulated expression in ER+ cancer or ER- cancer versus normal controls, and thus would miss critical information for elucidating the transcriptomic difference between the two subtypes.
Using microarray datasets from TCGA, we classified the genes dysregulated in both ER+ and ER- cancers versus normal controls into two classes: (i) genes dysregulated in the same direction but to a different extent, and (ii) genes dysregulated to opposite directions, and then validated the two classes in RNA-sequencing datasets of independent cohorts. We showed that the genes dysregulated to a larger extent in ER+ cancers than in ER- cancers enriched in glycerophospholipid and polysaccharide metabolic processes, while the genes dysregulated to a larger extent in ER- cancers than in ER+ cancers enriched in cell proliferation. Phosphorylase kinase and enzymes of glycosylphosphatidylinositol (GPI) anchor biosynthesis were upregulated to a larger extent in ER+ cancers than in ER- cancers, whereas glycogen synthase and phospholipase A2 were downregulated to a larger extent in ER+ cancers than in ER- cancers. We also found that the genes oppositely dysregulated in the two subtypes significantly enriched with known cancer genes and tended to closely collaborate with the cancer genes. Furthermore, we showed the possibility that these oppositely dysregulated genes could contribute to carcinogenesis of ER+ and ER- cancers through rewiring different subpathways.
GPI-anchor biosynthesis and glycogenolysis were elevated and hydrolysis of phospholipids was depleted to a larger extent in ER+ cancers than in ER- cancers. Our findings indicate that the genes oppositely dysregulated in the two subtypes are potential cancer genes which could contribute to carcinogenesis of both ER+ and ER- cancers through rewiring different subpathways.
直接比较雌激素受体阳性（ER+）和雌激素受体阴性（ER-）乳腺癌的基因表达谱，并不能确定这两种亚型之间差异表达的基因是由于 ER+癌症或 ER-癌症相对于正常对照的表达失调引起的，因此会错过阐明这两种亚型之间转录组差异的关键信息。
使用 TCGA 的微阵列数据集，我们将在 ER+和 ER-癌症与正常对照中均失调的基因分为两类：（i）以相同方向但不同程度失调的基因，和（ii）以相反方向失调的基因，然后在独立队列的 RNA 测序数据集中验证了这两类基因。我们表明，在 ER+癌症中比在 ER-癌症中失调程度更大的基因富集于甘油磷脂和多糖代谢过程，而在 ER-癌症中比在 ER+癌症中失调程度更大的基因富集于细胞增殖。磷酸化酶激酶和糖基磷脂酰肌醇（GPI）锚生物合成酶在 ER+癌症中比在 ER-癌症中上调程度更大，而糖原合酶和磷脂酶 A2 在 ER+癌症中比在 ER-癌症中下调程度更大。我们还发现，这两种亚型中相反失调的基因显著富集于已知的癌症基因，并倾向于与癌症基因密切合作。此外，我们表明这些相反失调的基因可能通过重新连接不同的亚通路，促进 ER+和 ER-癌症的发生。
GPI 锚生物合成和糖原分解在 ER+癌症中比在 ER-癌症中升高，而磷脂水解则减少。我们的研究结果表明，这两种亚型中相反失调的基因是潜在的癌症基因，它们可能通过重新连接不同的亚通路，促进 ER+和 ER-癌症的发生。
