Comprehensive analysis of PTEN status in breast carcinomas

Abstract

PTEN plays a well-established role in the negative regulation of the PI3K pathway, which is frequently activated in several cancer types, including breast cancer. A nuclear function in the maintenance of chromosomal stability has been proposed for PTEN but is yet to be clearly defined. In order to improve understanding of the role of PTEN in mammary tumorigenesis in terms of a possible gene dosage effect, its PI3K pathway function and its association with p53, we undertook comprehensive analysis of PTEN status in 135 sporadic invasive ductal carcinomas. Four PTEN status groups were defined; complete loss (19/ 135, 14%), reduced copy number (19/135, 14%), normal (86/135, 64%) and complex (11/135, 8%). Whereas the PTEN complete loss status was significantly associated with estrogen receptor (ER) negativity (p50.006) and in particular the basal-like phenotype (p<0.0001), a reduced PTEN copy number was not associated with hormone receptor status or a particular breast cancer subtype. Overall, PI3K pathway alteration was suggested to be involved in 59% (79/134) of tumors as assessed by human epidermal growth factor receptor 2 overexpression, PIK3CA mutation or a complete loss of PTEN. A complex PTEN status was identified in a tumor subgroup which displayed a specific, complex DNA profile at the PTEN locus with a strikingly similar highly rearranged pan-genomic profile. All of these tumors had relapsed and were associated with a poorer prognosis in the context of node negative disease (p51.4 3 10 213 ) thus may represent a tumor subgroup with a common molecular alteration which could be targeted to improve clinical outcome.Alterations in phosphatidylinositol 3-kinase (PI3K) pathway components have been described in breast cancer and can lead to hyperactivation of the pathway. Human epidermal growth factor receptor 2 (HER2) overexpression is observed in 15% of breast cancers. 1,2 Activating mutations in PIK3CA, which encodes the PI3K catalytic subunit, have been reported in approximately a quarter of breast tumors 3 and copy number gain of this gene has been identified in 1-14% of breast cancers. [4][5][6] Approximately one fifth of breast cancers are described as having loss of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression (range 4-48%) 6-15 and epigenetic silencing of the PTEN gene through promoter hypermethylation has been reported in 34% 16 and 48% 17 of breast cancers. Loss of heterozygosity at the PTEN locus is observed in 40% of invasive breast carcinomas 18,19 but mutations in this gene have only been identified in 2-9% of breast cancers 3,7,[20][21][22] suggesting that PTEN haploinsufficiency may have tumorigenic consequences. 23,24 Indeed, complete loss of Pten has been reported to oppose tumor progression in vitro and in a prostate-specific mouse model through induction of p53-dependant cellular senescence. 25 In addition to its function as a negative regulator of the PI3K pathway, a nuclear role for PTEN has been proposed. It has been reported to control chromosomal integrity t...

Correlative Analysis of Genetic Alterations and Everolimus Benefit in Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Results From BOLERO-2

“…[2][3][4][5][6][7][8][9] However, correlations between such genetic alteration data and clinical outcome in well-defined large clinical trial cohorts of any cancer have yet to be explored. We sequenced exons of cancer-related genes using NGS technology in archival tumor specimens from a subset of patients in BOLERO-2 and explored potential associations between PFS benefit from everolimus and genetic alterations in phosphoinositide 3-kinase (PI3K) and fibroblast growth factor receptor (FGFR) pathway genes.…”

Prognostic Role of PTEN Gene Expression and Length of Survival of Breast Cancer Patients in the North East of Iran

“…Comprehensive analysis of the PTEN gene has indicated that not only it is a tumour suppressor, but also it plays a role in breast cancer prognosis (Jones et al, 2013;Mandal et al, 2015). In the present study, PTEN gene was not expressed in patients in the progress stage of the disease (Stage IV).…”

“…Therefore, it is likely that one of the reasons for increased invasiveness in invasive ductal tumours is the lack of PTEN gene expression in them. Studies by Jones et al (2013) indicated that complete loss of the function of PTEN protein in tumours increases invasive power and significantly reduces the oestrogen receptors. In the present study, PTEN gene was expressed less in malignant breast tumours at higher grades.…”

MicroRNA-301a promotes cell proliferation via PTEN targeting in Ewing's sarcoma cells

“…Phosphatase and tensin homologue (PTEN) is considered as a tumor suppressor gene associated with the p53 signaling pathway (15,16). PTEN plays a vital role in regulating the cell cycle and inhibiting cell growth and division (17,18).…”