- 作者列表："Gu X","Wang B","Zhu H","Zhou Y","Horning AM","Huang TH","Chen Y","Houghton P","Lai Z","Michalek JE","Sun LZ
BACKGROUND:Aging is a comorbidity of breast cancer suggesting that aging-associated transcriptome changes may promote breast cancer progression. However, the mechanism underlying the age effect on breast cancer remains poorly understood. METHOD:We analyzed transcriptomics of the matched normal breast tissues from the 82 breast cancer patients in The Cancer Genome Atlas (TCGA) dataset with linear regression for genes with age-associated expression that are not associated with menopause. We also analyzed differentially expressed genes between the paired tumor and non-tumor breast tissues in TCGA for the identification of age and breast cancer (ABC)-associated genes. A few of these genes were selected for further investigation of their malignancy-regulating activities with in vitro and in vivo assays. RESULTS:We identified 148 upregulated and 189 downregulated genes during aging. Overlapping of tumor-associated genes between normal and tumor tissues with age-dependent genes resulted in 14 upregulated and 24 downregulated genes that were both age and breast cancer associated. These genes are predictive in relapse-free survival, indicative of their potential tumor promoting or suppressive functions, respectively. Knockdown of two upregulated genes (DYNLT3 and P4HA3) or overexpression of the downregulated ALX4 significantly reduced breast cancer cell proliferation, migration, and clonogenicity. Moreover, knockdown of P4HA3 reduced growth and metastasis whereas overexpression of ALX4 inhibited the growth of xenografted breast cancer cells in mice. CONCLUSION:Our study suggests that transcriptome alterations during aging may contribute to breast tumorigenesis. DYNLT3, P4HA3, and ALX4 play significant roles in breast cancer progression.
背景: 衰老是乳腺癌的共病，提示衰老相关的转录组改变可能促进乳腺癌的进展。然而，年龄对乳腺癌影响的潜在机制仍然知之甚少。 方法: 我们分析了癌症基因组图谱 (TCGA) 中 82 例乳腺癌患者的匹配正常乳腺组织的转录组学与绝经无关的年龄相关表达基因的线性回归数据集。我们还分析了 TCGA 中配对肿瘤和非肿瘤乳腺组织之间的差异表达基因，用于鉴定年龄和乳腺癌 (ABC) 相关基因。选择其中一些基因，用体外和体内试验进一步研究其恶性肿瘤调节活性。 结果: 我们在衰老过程中发现了 148 个上调基因和 189 个下调基因。正常和肿瘤组织之间肿瘤相关基因与年龄依赖性基因的重叠导致 14 个上调和 24 个下调的基因同时与年龄和乳腺癌相关。这些基因可预测无复发生存期，分别指示其潜在的肿瘤促进或抑制功能。敲除两个上调基因 (DYNLT3 和 P4HA3) 或过表达下调的 ALX4 可显著降低乳腺癌细胞增殖、迁移和克隆形成。此外，敲除 P4HA3 可减少生长和转移，而过表达 ALX4 可抑制小鼠异种移植乳腺癌细胞的生长。 结论: 我们的研究表明，衰老过程中的转录组改变可能有助于乳腺肿瘤的发生。DYNLT3 、 P4HA3 和 ALX4 在乳腺癌进展中起重要作用。
METHODS::The emerging significance of the bitter taste receptors (T2Rs) role in the extraoral tissues alludes to their potential role in many pathophysiological conditions. The dysregulation of T2R expression and function in disease conditions has now been demonstrated in airways diseases, neurological disorders, and in some cancers. However, the role of T2Rs in the pathophysiology of breast cancer is unexplored thus far. Previously, we demonstrated differential expression of the 25 T2Rs in breast cancer (BC) cells. Based on our previous findings we selected two T2Rs, T2R4 and T2R14 for this work. The objective of the current study is to investigate the expression of T2R4 and T2R14 in BC clinical samples and to examine their physiological role using highly metastatic BC and non-cancerous cell lines. Using approaches, which involve receptor knockdown, pharmacological activation and biochemical assays we report that (i) T2R4 and T2R14 expression patterns are dissimilar, with decreased levels of T2R4 and increased levels of T2R14 in BC clinical samples compared to non-cancerous controls. (ii) Activation of T2Rs with their respective agonist elicited physiological responses in metastatic breast cancer cells, and no responses were seen in non-tumorigenic breast epithelial cells. (iii) Agonist activation of T2Rs (irrespective of T2R subtype) induced anti-proliferative, pro-apoptotic, and anti-migratory responses in highly metastatic breast cancer cells. Taken together, our findings demonstrate that the chemosensory T2R signaling network is involved in evoking physiological responses in the metastatic breast cancer cell line.
METHODS::RAD50 is commonly depleted in basal-like breast cancer with concomitant absence of INPP4B and several tumor suppressors such as BRCA1 and TP53. Our previous study revealed that INPP4B and RAD50 interact and such an interaction is associated with breast cancer survival at the transcriptional, translational and genomic levels. In the present study, we explored single nucleotide polymorphisms (SNPs) of these two genes that have synergistic effects on breast cancer survival to decipher mechanisms driving their interactions at the genetic level. The Cox's proportional hazards model was used to test whether SNPs of these two genes are interactively associated with breast cancer survival, following expression quantitative trait loci (eQTL) analysis and functional investigations. Our study revealed two disease-associating blocks, each encompassing five and two non-linkage disequilibrium linked SNPs of INPP4B and RAD50, respectively. Concomitant presence of any rare homozygote from each disease-associating block is synergistically prognostic of poor breast cancer survival. Such synergy is mediated via bypassing pathways controlling cell proliferation and DNA damage repair, which are represented by INPP4B and RAD50. Our study provided genetic evidence of interactions between INPP4B and RAD50, and deepened our understandings on the orchestrated genetic machinery governing tumor progression.
METHODS:BACKGROUND:Increased usage of genomic risk assessment assays suggests increased reliance on data provided by these assays to guide therapy decisions. The current study aimed to assess the change in treatment decision and physician confidence based on the 70-gene risk of recurrence signature (70-GS, MammaPrint) and the 80-gene molecular subtype signature (80-GS, BluePrint) in early stage breast cancer patients. METHODS:IMPACt, a prospective, case-only study, enrolled 452 patients between November 2015 and August 2017. The primary objective population included 358 patients with stage I-II, hormone receptor-positive, HER2-negative breast cancer. The recommended treatment plan and physician confidence were captured before and after receiving results for 70-GS and 80-GS. Treatment was started after obtaining results. The distribution of 70-GS High Risk (HR) and Low Risk (LR) patients was evaluated, in addition to the distribution of 80-GS compared to IHC status. RESULTS:The 70-GS classified 62.5% (n = 224/358) of patients as LR and 37.5% (n = 134/358) as HR. Treatment decisions were changed for 24.0% (n = 86/358) of patients after receiving 70-GS and 80-GS results. Of the LR patients initially prescribed CT, 71.0% (44/62) had CT removed from their treatment recommendation. Of the HR patients not initially prescribed CT, 65.1% (41/63) had CT added. After receiving 70-GS results, CT was included in 83.6% (n = 112/134) of 70-GS HR patient treatment plans, and 91.5% (n = 205/224) of 70-GS LR patient treatment plans did not include CT. For patients who disagreed with the treatment recommended by their physicians, most (94.1%, n = 16/17) elected not to receive CT when it was recommended. For patients whose physician-recommended treatment plan was discordant with 70-GS results, discordance was significantly associated with age and lymph node status. CONCLUSIONS:The IMPACt trial showed that treatment plans were 88.5% (n = 317/358) in agreement with 70-GS results, indicating that physicians make treatment decisions in clinical practice based on the 70-GS result. In clinically high risk, 70-GS Low Risk patients, there was a 60.0% reduction in treatment recommendations that include CT. Additionally, physicians reported having greater confidence in treatment decisions for their patients in 72% (n = 258/358) of cases after receiving 70-GS results. TRIAL REGISTRATION:"Measuring the Impact of MammaPrint on Adjuvant and Neoadjuvant Treatment in Breast Cancer Patients: A Prospective Registry" (NCT02670577) retrospectively registered on Jan 27, 2016.