Differential expressions of cancer-associated genes, including histone deacetylases (HDACs), were identified in distinctive molecular subtypes of breast cancer. Compared with hormone receptor-positive breast cancer, triple-negative (TNBC, ER−PR−HER2−) is the most aggressive form of breast cancer.
Aims:
To determine the association of HDAC7 mRNA expression levels with clinicopathological features and patients' survival with TNBC or ER+PR+HER2− breast cancers.
Methods:
Total RNA was extracted from 61 TNBC and 74 ER+PR+Her2− tumors. Relative gene expression was evaluated by SYBR Green RT-PCR, normalized to glyceraldehyde-3-phosphate dehydrogenase. The HDAC7 mRNA expression was defined as high or low, according to receiver operating characteristic analysis. Kaplan-Meier and Cox regression analyses for overall survival were assessed to evaluate the prognostic relevance of HDAC7 overexpression.
Results:
The HDAC7 overexpression was predominantly found in invasive ductal carcinomas (p = 0.023), high histologic grade (p = 0.007), and high nuclear grade tumors (p = 0.030). TNBC subtypes had a significantly lower mean HDAC7 gene expression compared with ER+PR+HER2− tumors (p = 0.005). However, HDAC7 overexpression predicted unfavorable survival of TNBC patients (p = 0.003). Multivariate Cox regression analysis indicated that recurrences (hazard ratio [HR] = 5.432, p = 0.003), and HDAC7 overexpression (HR = 9.287, p = 0.033) persisted as independent prognostic factors for poor survival of TNBC patients.
Conclusions:
HDAC7 mRNA overexpression is associated with poor survival in patients with TNBC tumors.
Get full access to this article
View all access options for this article.
References
1.
AndersenCL, JensenJL, ØrntoftTF (2004) Normalization of real-time quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Res, 64:5245-5250.
2.
Barneda-ZahoneroB, CollazoO, AzagraA, et al. (2015) The Transcriptional repressor HDAC7 promotes apoptosis and C-Myc downregulation in particular types of leukemia and lymphoma. Cell Death Dis, 6:e1635.
3.
Barneda-ZahoneroB, ParraM (2012) Histone deacetylases and cancer. Mol Oncol, 6:579-589.
4.
CasliniC, HongS, BanYJ, et al. (2019) HDAC7 regulates histone 3 lysine 27 acetylation and transcriptional activity at super-enhancer-associated genes in breast cancer stem cells. Oncogene, 38:6599-6614.
5.
ChangS, YoungBD, LiS, et al. (2006) Histone deacetylase 7 maintains vascular integrity by repressing matrix metalloproteinase 10. Cell, 126:321-334.
6.
DokmanovicM, PerezG, XuW, et al. (2007) Histone deacetylase inhibitors selectively suppress expression of HDAC7. Mol Cancer Ther, 6:2525-2534.
7.
EdiriweeraMK, TennekoonKH, SamarakoonR (2019) Emerging role of histone deacetylase inhibitors as anti-breast-cancer agents. Drug Discov Today, 24:685-702.
8.
GaoS, LiuH, HouS, et al. (2018) MiR-489 suppresses tumor growth and invasion by targeting HDAC7 in colorectal cancer. Clin Transl Oncol, 20:703-712.
9.
HuangJP, LingK (2017) EZH2 and histone deacetylase inhibitors induce apoptosis in triple negative breast cancer cells by differentially increasing H3 Lys27 acetylation in the BIM gene promoter and enhancers. Oncol Lett, 14:5735-5742.
10.
LeiY, LiuL, ZhangS, et al. (2017) Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation. Mol Cancer, 6:170.
11.
LiB, SamantaA, SongX, et al. (2007) FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression. Proc Natl Acad Sci U S A, 104:4571-4576.
12.
LiQG, XiaoT, ZhuW, et al. (2020) HDAC7 promotes the oncogenicity of nasopharyngeal carcinoma cells by miR-4465-EphA2 signaling axis. Cell Death Dis, 11:322.
13.
LiuLL, ZhaoH, MaTF, et al. (2015) Identification of valid reference genes for the normalization of RT-qPCR expression studies in human breast cancer cell lines treated with and without transient transfection. PLoS One, 10:e0117058.
14.
MalikS, JiangS, GareeJP, et al. (2010) Histone deacetylase 7 and FoxA1 in estrogen-mediated repression of RPRM. Mol Cell Biol, 30:399-412.
15.
MorenoDA, ScrideliCA, CortezMAA, et al. (2010) Differential expression of HDAC3, HDAC7 and HDAC9 is associated with prognosis and survival in childhood acute lymphoblastic leukaemia. Br J Haematol, 150:665-673.
16.
MottetD, BellahcèneA, PirotteS, et al. (2007) Histone deacetylase 7 silencing alters endothelial cell migration, a key step in angiogenesis. Circ Res, 101:1237-1246.
17.
ParkS, KooJS, KimMS, et al. (2012) Characteristics and outcomes according to molecular subtypes of breast cancer as classified by a panel of four biomarkers using immunohistochemistry. Breast, 21:50-57.
18.
PfafflMW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucl Acids Res, 29:e45.
19.
PfafflMW, TichopadA, PrgometC, NeuviansTP (2004) Determination of stable housekeeping genes, differentially regulated target genes and sample integrity: bestKeeper-Excel-based tool using pair-wise correlations. Biotechnol Lett, 26:509-515.
20.
SabnisGJ, GoloubevaO, ChumsriS, et al. (2011) Functional activation of the estrogen receptor-α and aromatase by the HDAC inhibitor entinostat sensitizes ER-negative tumors to letrozole. Cancer Res, 71:1893-1903.
21.
SangY, SunL, WuY, et al. (2019) Histone deacetylase 7 inhibits plakoglobin expression to promote lung cancer cell growth and metastasis. Int J Oncol, 54:1112-1122.
22.
SorlieT, TibshiraniR, ParkerJ, et al. (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A, 100:8418-8423.
23.
SuY, HopfingerNR, NguyenTD, et al. (2018) Epigenetic reprogramming of epithelial mesenchymal transition in triple negative breast cancer cells with DNA methyltransferase and histone deacetylase inhibitors. J Exp Clin Cancer Res, 37:314.
24.
TriversKF, LundMJ, PorterPL, et al. (2009) The epidemiology of triple-negative breast cancer, including race. Cancer Causes Control, 20:1071-1082.
25.
ValentiMT, BertoldoF, Dalle CarbonareL, et al. (2006) The effect of bisphosphonates on gene expression: GAPDH as a housekeeping or a new target gene?. BMC Cancer, 6:49.
26.
VillagraA, ChengF, WangH-W, et al. (2009) The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance. Nat Immunol, 10:92-100.
27.
WeichertW (2009) HDAC expression and clinical prognosis in human malignancies. Cancer Lett, 280:168-176.
28.
WiechmannL, SampsonM, StempelM, et al. (2009) Presenting features of breast cancer differ by molecular subtype. Ann Surg Oncol, 16:2705-2710.
29.
WittAE, LeeC-W, LeeTI, et al. (2017) Identification of a cancer stem cell-specific function for the histone deacetylases, HDAC1 and HDAC7, in breast and ovarian cancer. Oncogene, 36:1707-1720.
30.
WuMY, FuJ, XiaoX, et al. (2014) MiR-34a regulates therapy resistance by targeting HDAC1 and HDAC7 in breast cancer. Cancer Lett, 354:311-319.
31.
XiaoY, XuC, PingY, et al. (2011) Differential expression pattern-based prioritization of candidate genes through integrating disease-specific expression data. Genomics, 98:64-71.
32.
YanoM, YasudaM, SakakiM, et al. (2018) Association of histone deacetylase expression with histology and prognosis of ovarian cancer. Oncol Lett, 15:3524-3531.
33.
YuY, CaoF, YuX, et al. (2017) The expression of HDAC7 in cancerous gastric tissues is positively associated with distant metastasis and poor patient prognosis. Clin Transl Oncol, 19:1045-1054.
34.
ZhangH, LiL, YuanC, et al. (2020) MiR-489 inhibited the development of gastric cancer via regulating HDAC7 and PI3K/AKT pathway. World J Surg Oncol, 18:73.
35.
ZhangQ, WangT, GengC, et al. (2018) Exploratory clinical study of chidamide, an oral subtype-selective histone deacetylase inhibitor, in combination with exemestane in hormone receptor-positive advanced breast cancer. Chin J Cancer Res, 30:605-612.
36.
ZhouQ, AtadjaP, DavidsonNE (2007) Histone deacetylase inhibitor LBH589 reactivates silenced estrogen receptor alpha (ER) gene expression without loss of DNA hypermethylation. Cancer Biol Ther, 6:64-69.
37.
ZhuC, ChenQ, XieZ, et al. (2011) The role of histone deacetylase 7 (HDAC7) in cancer cell proliferation: regulation on c-Myc. J Mol Med, 89:279-289.
