PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas

Lee, Jong Woo; Soung, Young Hwa; Kim, Su Young; Lee, Hae Woo; Park, Won Sang; Nam, Suk Woo; Kim, Sang Ho; Lee, Jung Young; Yoo, Nam Jin; Lee, Sug Hyung

doi:10.1038/sj.onc.1208304

Cited by 479 publications

(372 citation statements)

References 21 publications

Supporting

Mentioning

344

Contrasting

Unclassified

Order By: Relevance

“…Deregulation of this pathway leads to upregulation of AKT signalling cascades was commonly found in variety of human cancers including breast carcinoma (Vivanco and Sawyers, 2002;Lee et al, 2005;Levine et al, 2005). It was evidenced that AKT signalling was transduced from upstream PI3-K (Franke et al, 1995).…”

Section: Phosphorylation Of Akt In Breast Carcinomamentioning

confidence: 97%

“…AKT is activated in response to survival signals from growth factors or cytokines via mechanisms involving PI3-K and PDK-1 (Alessi et al, 1997;Franke et al, 1997;Kulik et al, 1997;Bellacosa et al, 1998). Upregulation of AKT by mutation of PTEN (a tumour suppressor gene that antagonises AKT pathway) or amplification PIK3CA (encodes catalytic subunit of PI3-K) were reported in a number of human cancers including breast carcinoma (Vivanco and Sawyers, 2002;Lee et al, 2005;Levine et al, 2005). Regarding other receptor tyrosine kinases, breast cancer cells also produce platelet-derived growth factor (PDGF) and its receptors, through autocrine or paracrine mechanisms, to modulate growth, survival, and differentiation of breast tissues (Shao et al, 2000).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

et al. 2005

View full text Add to dashboard Cite

Activation of kinases signalling pathways contributes to various malignant phenotypes in human cancers, including breast tumour. To examine the possible activation of these signalling molecules, we examined the phosphorylation status in 12 protein kinases and transcription factors in normal primary human mammary epithelial cells, telomerase-immortalised human breast epithelial cell line, and two breast cancer lines, MDA-MB-468 and MCF-7, using Kinexus phosphorylated protein screening assays. The phosphorylation of FAK, mTOR, p70S6K, and PDK-1 were elevated in both breast cancer cell lines, whereas the phosphorylation of AKT, EGFR, ErbB2/ Her2, PDGFR, Shc, and Stat3 were elevated in only one breast cancer line compared to normal primary mammary epithelial cells and telomerase-immortalised breast epithelial cells. The same findings were confirmed by Western blotting and by kinase assays. We further substantiated the phosphorylation status of these molecules in tissue microarray slides containing 89 invasive breast cancer tissues as well as six normal mammary tissues with immunohistochemistry staining using phospho-specific antibodies. Consistent findings were obtained as greater than 70% of invasive breast carcinomas expressed moderate to high levels of phosphorylated PDK-1, AKT, p70S6K, and EGFR. In sharp contrast, phosphorylation of the same proteins was nearly undetectable or was at low levels in normal mammary tissues under the same assay. Elevated phosphorylation of PDK-1, AKT, mTOR, p70S6K, S6, EGFR, and Stat3 were highly associated with invasive breast tumours (Po0.05). Taken together, our results suggest that activation of these kinase pathways by phosphorylation may in part account for molecular pathogenesis of human breast carcinoma. Particularly, moderate to high level of PDK-1 phosphorylation was found in 86% of high-grade metastasised breast tumours. This is the first report demonstrating phosphorylation of PDK-1 is frequently elevated in breast cancer with concomitantly increased phosphorylation of downstream kinases, including AKT, mTOR, p70S6K, S6, and Stat3. This finding thus suggested PDK-1 may promote oncogenesis in part through the activation of AKT and p70S6K and rationalised that PDK-1 as well as downstream components of PDK-1 signalling pathway may be promising therapeutic targets to treat breast cancer. Breast cancer remains to be a major cause of death in women worldwide, despite improvements in cancer prevention, early detection, treatment, and understanding the molecular pathogenesis. It hence demands an urgent need to unveil the exact mechanism of oncogenesis and tumour progression, which may prelude the development of new strategies for treatment. Breast carcinoma emerges through multistep processes progressing from hyperplasia to premalignant change, in situ carcinoma, invasion, and distal metastasis, in concomitant with gain of oncogenic activities and loss of tumour suppressor gene functions.Protein kinases have been implicated in playing crucial roles in regulating cell growth, met...

show abstract

Section: Phosphorylation Of Akt In Breast Carcinomamentioning

confidence: 97%

mentioning

confidence: 99%

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Overall, these results suggest alteration of the TGFb pathway in 10-30% of the HCC cases. Recently, mutations activating phosphatidylinositol 3-kinase (PIK3CA gene) have been found in 36% of HCC in Korea (Lee et al, 2005) and these mutations activating the AKT pathway have been found in less than 5% of HCC in France (unpublished results).…”

Section: )mentioning

confidence: 98%

Genetics of hepatocellular tumors

2006

View full text Add to dashboard Cite

Numerous genetic alterations are accumulated during the process of hepatocarcinogenesis. These genetic alterations can be divided into two groups. The first set of genetic alterations is specific of hepatocellular tumor risk factors. It includes integration of hepatitis B virus (HBV) DNA, R249S TP53 (tumor protein p53) mutation in aflatoxin B1-exposed patients, KRAS mutations related to vinyl chloride exposure, hepatocyte nuclear factor 1a (HNF1a) mutations associated to hepatocellular adenomas and adenomatosis polyposis coli (APC) germline mutations predisposing to hepatoblastomas. The second set of genetic alterations are etiological nonspecific, it includes recurrent gains and losses of chromosomes, alteration of TP53 gene, activation of WNT/b-catenin pathway through CTNNB1/b-catenin and AXIN (axis inhibition protein) mutations, inactivation of retinoblastoma and IGF2R (insulin-like growth factor 2 receptor) pathways through inactivation of RB1 (retinoblastoma 1), P16 and IGF2R. Comprehensive analyses of these genetic alterations have defined two pathways of hepatocarcinogenesis according to the presence or the absence of chromosomal instability. Hepatitis B virus and poorly differentiated tumors are related to chromosome instable tumors associated with frequent TP53 mutations, whereas non-HBV and well-differentiated tumors are related to chromosomal stable samples that are frequently b-catenin activated. These classifications have clinical relevance as genetic alterations may also be related to prognosis.

show abstract

“…These cancers include cancer of the colon, stomach, breast, brain, lung, ovary and thyroid gland (Broderick et al, 2004;Campbell et al, 2004;Lee et al, 2005;Levine et al, 2005;Li et al, 2005;Velho et al, 2005). PIK3CA mutations have been reported to occur in sporadic colorectal cancer (CRC) at a frequency of 31.6% , 18.8% (Campbell et al, 2004) or 13.6% (Velho et al, 2005), generally at a later stage of tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population

Abubaker¹,

Bavi²,

Al-harbi³

et al. 2008

Oncogene

View full text Add to dashboard Cite

Activation of the phosphatidylinositol 3 0 -kinase (PI3K)/ AKT pathway results in an increase in cell proliferation and survival. Somatic mutations within the PI3K catalytic subunit, PIK3CA are common cause of increasing PI3K activity and are believed to be oncogenic in many cancer types. Few reports addressed the association between PIK3CA mutations and tumor progression specifically in microsatellite instable (MSI) colorectal cancer (CRC). In the present study, we have evaluated PIK3CA mutational status in a series of 410 Middle Eastern CRC and 13 colon cell lines to study the prevalence of PIK3CA mutations in MSI cases, PTEN expression in CRC and possibility of therapeutic targeting of this set of patients. PIK3CA mutations were found in four of the cell lines tested and 51 colorectal carcinomas (12.2%). Three of these four mutated cell lines were MSI. PTEN was inactivated in 66.1% of the CRC. Furthermore, we observed a strong association between PIK3CA mutations and MSI status (P ¼ 0.0046) while PTEN loss was more frequent in microsatellite stable (MSS) CRC (P ¼ 0.043). A high prevalence of genetic alterations in PI3K/AKT pathway in Saudi cohort of CRC, predominance of PIK3CA mutations in the MSI subgroup and their possible involvement in development/progression of this subset of CRC are some of the significant findings of our study.

show abstract

PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas

Cited by 479 publications

References 21 publications

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

Genetics of hepatocellular tumors

Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population

Contact Info

Product

Resources

About