The mRNA expression of SETD2 in human breast cancer: correlation with clinico-pathological parameters

Abstract

BackgroundSET domain containing protein 2 (SETD2) is a histone methyltransferase that is involved in transcriptional elongation.There is evidence that SETD2 interacts with p53 and selectively regulates its downstream genes. Therefore, it could be implicated in the process of carcinogenesis. Furthermore, this gene is located on the short arm of chromosome 3p and we previously demonstrated that the 3p21.31 region of chromosome 3 was associated with permanent growth arrest of breast cancer cells. This region includes closely related genes namely: MYL3, CCDC12, KIF9, KLHL18 and SETD2. Based on the biological function of these genes, SETD2 is the most likely gene to play a tumour suppressor role and explain our previous findings.Our objective was to determine, using quantitative PCR, whether the mRNA expression levels of SETD2 were consistent with a tumour suppressive function in breast cancer. This is the first study in the literature to examine the direct relationship between SETD2 and breast cancer.MethodsA total of 153 samples were analysed.The levels of transcription of SETD2 were determined using quantitative PCR and normalized against (CK19).Transcript levels within breast cancer specimens were compared to normal background tissues and analyzed against conventional pathological parameters and clinical outcome over a 10 year follow-up period.ResultsThe levels of SETD2 mRNA were significantly lower in malignant samples (p = 0.0345) and decreased with increasing tumour stage.SETD2 expression levels were significantly lower in samples from patients who developed metastasis, local recurrence, or died of breast cancer when compared to those who were disease free for > 10 years (p = 0.041).ConclusionThis study demonstrates a compelling trend for SETD2 transcription levels to be lower in cancerous tissues and in patients who developed progressive disease. These findings are consistent with a possible tumour suppressor function of this gene in breast cancer.

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

“…In human development, germline mutations in SETD2 cause an overgrowth condition with features similar to Sotos syndrome [91]. Underexpression and mutation of SETD2 are associated with poor prognosis in breast and renal cancer, GI stromal tumors and acute leukemia [92][93][94][95][96]. SETD2 mutations are more common in leukemias with MLL rearrangements (22%) than leukemias without such rearrangements (5%), and SETD2 loss cooperates with MLL fusions such as MLL-AF9 and MLL-NRIP to create a more aggressive leukemia with increased self-renewal of leukemia stem cells [97].…”

The epigenetic landscape of renal cancer

“…SETD2 and its splice variants encode enzymes that depose trimethylated histone H3 lysine 36 marks 153 . SETD2 is mutated in non-renal tumours [154][155][156] , and is biallelically inactivated in 3-12% of RCCs 4,12,13,143,157 . SETD2 mutations are associated with genome-wide loss of non-promoter DNA methylation in RCC 4 , and loss of SETD2 is sufficient to reduce the levels of the histone mark H3K36Me3 across the genome 158 .…”

Increased insulin-like growth factor-1 receptor mRNA expression predicts poor survival in immunophenotypes of early breast carcinoma

“…[9][10][11][12] Recent epidemiological and clinico-pathological data have supported the role of the insulin-like growth factor-1 (IGF1R) signaling system on tumor development and progression. [13][14][15][16][17] In breast carcinoma, high levels of IGF1R have been detected in 30-82%, 18,19 but its prognostic value is controversial. [20][21][22][23][24][25][26][27] Emerging experimental and clinical data suggest that the IGF1R and ER/PR pathways are interactive.…”