The 17q23 Amplicon and Breast Cancer

Sinclair, Colleen; Rowley, Matthew; Naderi, Ali; Couch, Fergus J.

doi:10.1023/a:1023081624133

Cited by 125 publications

(102 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Thus, it would be of interest to know whether a simultaneous It remains to be determined whether there is an oncogene within the 17q23 breast cancer amplicon whose overexpression could drive tumorigenesis in transgenic mice. The 17q23 amplification occurs fairly frequently (B18%) in primary human breast cancers (Kallioniemi et al, 1994;Sinclair et al, 2003) and there are three potential oncogenes, RPS6KB1, TBX-2 and WIP1, which have been identified within this genomic locus (Sinclair et al, 2003). However, overexpression of either WIP1, Tbx2 or both in MMTVtransgenic mice is not sufficient for tumor formation (present study and data not shown).…”

mentioning

confidence: 47%

“…The initial observation of regional gain at chromosome 17q22-23 using a comparative genomic hybridization (CGH) technique detected amplification in B18% of primary breast tumors (Kallioniemi et al, 1994), giving its name to the locus as the 17q23 breast cancer amplicon. Three potential oncogenes, RPS6KB1, TBX-2 and WIP1 have been found within this genomic locus at chromosome 17q22-23 (Sinclair et al, 2003). However, it remains uncertain whether any of these oncogenes can induce mammary gland tumors when overexpressed in mice.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The role of the MKK6/p38 MAPK pathway in Wip1-dependent regulation of ErbB2-driven mammary gland tumorigenesis

et al. 2006

View full text Add to dashboard Cite

There is increasing evidence for the role of wild-type p53 induced phosphatase 1 (Wip1) phosphatase in the regulation of tumorigenesis. To evaluate Wip1 as a breast cancer oncogene, we generated a mouse strain with targeted expression of Wip1 to the breast epithelium. We found that these mice are prone to cancer when intercrossed with transgenics expressing the ErbB2 oncogene but not conditional knockouts for Brca2. This tumor-prone phenotype of Wip1 is fully eliminated through attenuation of proliferation by activating the MKK6/p38 mitogenactivated protein kinases (MAPK) cascade in mice bearing a constitutively active form of MKK6. We propose that Wip1 phosphatase operates within the MKK6/p38 MAPK signaling pathway to promote ErbB2-driven mammary gland tumorigenesis.

show abstract

mentioning

confidence: 47%

mentioning

confidence: 99%

The role of the MKK6/p38 MAPK pathway in Wip1-dependent regulation of ErbB2-driven mammary gland tumorigenesis

et al. 2006

View full text Add to dashboard Cite

show abstract

“…The overexpression of Wip1 is likely to be oncogenic given its antagonism of key proteins involved in maintaining genomic stability. Indeed, the Wip1 gene at human chromosome 17q23 is amplified in 15% of human breast cancers, and its overexpression is found in an aggressive subset of breast, prostate, ovarian and brain cancers of poor prognosis (Hirasawa et al, 2003;Saito-Ohara et al, 2003;Sinclair et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase

et al. 2006

View full text Add to dashboard Cite

We previously demonstrated that type 2C protein phosphatases (PP2C) Ptc2 and Ptc3 are required for DNA checkpoint inactivation after DNA double-strand break repair or adaptation in Saccharomyces cerevisiae. Here, we show the conservation of this pathway in mammalian cells. In response to DNA damage, ataxia telangiectasia mutated (ATM) phosphorylates the Chk2 tumour suppressor kinase at threonine 68 (Thr68), allowing Chk2 kinase dimerization and activation by autophosphorylations in the T-loop. The oncogenic protein Wip1, a PP2C phosphatase, binds Chk2 and dephosphorylates phosphoThr68. Consequently, Wip1 opposes Chk2 activation by ATM after ionizing irradiation of cells. In HCT15 colorectal cancer cells corrected for functional Chk2 activity, Wip1 overexpression suppressed the contribution of Chk2 to the G2/M DNA damage checkpoint. These results indicate that Wip1 is one of the phosphatases regulating the activity of Chk2 in response to DNA damage.

show abstract

“…PS6K is a ribosomal protein that is involved in the progression from the G1 to S phase of the cell cycle. It is rapidly activated in response to mitogenic stimuli, for example, growth factors, cytokines, and oncogene products (Grove et al, 1991;Lane et al, 1993;Chou et al, 1995;Grammer et al, 1996;Thomas et al, 1997;Couch et al, 1999;Barlund et al, 2000b;Wu et al, 2000;Latham et al, 2001;Monni et al, 2001;Andersen et al, 2002;Li et al, 2002;Sinclair et al, 2002;Sinclair et al, 2003).…”

mentioning

confidence: 99%

Overexpression of P70 S6 kinase protein is associated with increased risk of locoregional recurrence in node-negative premenopausal early breast cancer patients

et al. 2004

View full text Add to dashboard Cite

The RPS6KB1 gene is amplified and overexpressed in approximately 10% of breast carcinomas and has been found associated with poor prognosis. We studied the prognostic significance of P70 S6 kinase protein (PS6K) overexpression in a series of 452 nodenegative premenopausal early-stage breast cancer patients (median follow-up: 10.8 years). Immunohistochemistry was used to assess PS6K expression in the primary tumour, which had previously been analysed for a panel of established prognostic factors in breast cancer. In a univariate analysis, PS6K overexpression was associated with worse distant disease-free survival as well as impaired locoregional control (HR 1.80, P 0.025 and HR 2.50, P 0.006, respectively). In a multivariate analysis including other prognostic factors, PS6K overexpression remained an independent predictor for poor locoregional control (RR 2.67, P 0.003). To our knowledge, P70 S6 kinase protein is the first oncogenic marker that has prognostic impact on locoregional control and therefore may have clinical implications in determining the local treatment strategy in early-stage breast cancer patients. The treatment of breast cancer is guided by risk factors. Approximately 70% of all node-negative breast cancer patients can be cured by locoregional therapy alone. This automatically implies that the remaining 30% of these patients will develop a recurrence despite adequate locoregional therapy. Currently, treatment strategy in breast cancer is based upon tumour stage, grade, and hormone receptor status. Additional prognostic factors are greatly needed, first to select those patients who might benefit from adjuvant systemic therapy and second to optimise locoregional therapy in order to avoid locoregional recurrences.The prognostic significance of a considerable number of tumour markers has already been investigated but to date, none of these factors can be used to guide the treatment of primary breast cancer.A recent study by Barlund et al (2000a) demonstrated that amplification of a putative tumour marker called P70 S6 kinase protein (PS6K) might be associated with poor outcome in breast cancer. In addition, the authors reported that RPS6KB1 gene amplification and PS6K overexpression are significantly correlated.The RPS6KB1 gene is located at 17q23 and amplified in approximately 10% of all primary breast cancer cases. PS6K is a ribosomal protein that is involved in the progression from the G1 to S phase of the cell cycle. It is rapidly activated in response to mitogenic stimuli, for example, growth factors, cytokines, and oncogene products (Grove et

show abstract

The 17q23 Amplicon and Breast Cancer

Cited by 125 publications

References 45 publications

The role of the MKK6/p38 MAPK pathway in Wip1-dependent regulation of ErbB2-driven mammary gland tumorigenesis

The role of the MKK6/p38 MAPK pathway in Wip1-dependent regulation of ErbB2-driven mammary gland tumorigenesis

The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase

Overexpression of P70 S6 kinase protein is associated with increased risk of locoregional recurrence in node-negative premenopausal early breast cancer patients

Contact Info

Product

Resources

About