Comprehensive copy number and gene expression profiling of the 17q23 amplicon in human breast cancer

Monni, Outi; Bärlund, Maarit; Mousses, Spyro; Kononen, Juha; Sauter, Guido; Heiskanen, Mervi; Paavola, Paulina; Avela, Kristiina; Chen, Yidong; Bittner, Michael; Kallioniemi, Anne

doi:10.1073/pnas.091582298

Cited by 204 publications

(164 citation statements)

References 35 publications

(33 reference statements)

Supporting

Mentioning

153

Contrasting

Unclassified

Order By: Relevance

“…Although the Erbb2 gene is amplified in many somatic breast carcinomas, evidence suggests that this locus is not commonly gained or overexpressed in BRCA1-related breast or ovarian cancers Rhei et al, 1998;Vaziri et al, 2001). Studies that correlate gene amplification with gene overexpression point to another gene on 17q23, orthologous to mouse 11D-E (Wu et al, 2000;Monni et al, 2001). Therefore this model could be used to confirm the relevance of candidate genes in human BRCA1-related breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the commonly gained region on chromosome 11 centered on bands 11D-E, a region that is orthologous to human chromosome 17q11-qter, which is frequently amplified in human breast carcinomas (Bieche and Lidereau, 1995;Ried et al, 1995;Barlund et al, 1997). Of note, the amplicon on chromosome band 17q23, associated with poor prognosis in human cancers, was recently shown to have a limited number of highly expressed genes that may contribute to the more aggressive phenotype (Monni et al, 2001). Another analogy extends to the c-Myc oncogene, another common target for amplification in human breast cancer, both in sporadic and BRCA1-mutation associated tumors (Nass and Dickson, 1997).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mammary tumors in mice conditionally mutant for Brca1 exhibit gross genomic instability and centrosome amplification yet display a recurring distribution of genomic imbalances that is similar to human breast cancer

et al. 2002

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mammary tumors in mice conditionally mutant for Brca1 exhibit gross genomic instability and centrosome amplification yet display a recurring distribution of genomic imbalances that is similar to human breast cancer

et al. 2002

View full text Add to dashboard Cite

“…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

“…[52][53][54][55] Region 17q23 is amplified in several breast cancer cell lines and in up to 30% of primary tumors, 56 while S6K1 is overexpressed and hyperactivated in the majority of cell lines and primary tumors with this amplification, more predominantly in breast cancer with BRCA1/2 mutations. 19,51,52,[57][58][59] In fact, BRCA1/2 mutations may be directly responsible for chromosomal breakage and amplifications in the 17q23 region. 60 Estrogenic regulation of S6K1 expression within the 17q23 amplicon.…”

Section: S6k1 In Er-positivementioning

confidence: 99%

The role of S6K1 in ER-positive breast cancer

Holz

2012

Cell Cycle

View full text Add to dashboard Cite

T he 40S ribosomal S6 kinase 1 (S6K1) is a conserved serine/threonine protein kinase that belongs to the AGC family of protein kinases, which also includes Akt and many others. S6K1 is the principal kinase effector downstream of the mammalian target of rapamycin complex 1 (mTORC1). S6K1 is sensitive to a wide range of signaling inputs, including growth factors, amino acids, energy levels and hypoxia. S6K1 relays these signals to regulate a growing list of substrates and interacting proteins in control of oncogenic processes, such as cell growth and proliferation, cell survival and apoptosis and cell migration and invasion. Several lines of evidence suggest an important role for S6K1 in estrogen receptor (ER)-positive breast cancer. S6K1 directly phosphorylates and activates ERα. Furthermore, S6K1 expression is estrogenically regulated. Therefore, hyperactivation of mTORC1/ S6K1 signaling may be closely related to ER-positive status in breast cancer and may be utilized as a marker for prognosis and a therapeutic target. IntroductionThe mTORC1 signaling pathway. Since its cloning and biochemical purification almost 20 y ago, mTOR, a conserved protein kinase, emerged as a central node in the plexus coordinating cellular growth and proliferation in response to numerous extracellular cues, including nutrient availability and growth stimuli. In eukaryotic cells, mTOR exists in two complexes. mTORC1 and mTORC2 consist of distinct sets of proteins and perform non-redundant functions. 1 a naturally derived inhibitor of mTORC1 and an inhibitor of cell proliferation, as manifested by its potent immunosuppressive properties and activity against solid tumors. 2 Growth factor signaling to mTORC1 is primarily mediated by the phosphatidylinositol-3 kinase (PI3K) pathway and inactivation of the tuberous sclerosis complex protein TSC2 (tuberin). As illustrated in Figure 1, in response to extracellular activating stimuli, PI3K mediates cell membrane recruitment and activation of the serine/threonine protein kinases phosphatidylinositol-dependent kinase-1 (PDK1) and Akt. 3,4 The lipid phosphatase PTEN opposes the action of PI3K. TSC2 functions as a heterodimer with TSC1 (hamartin) to negatively regulate mTORC1 signaling by acting as a GTPase-activating protein (GAP) for the small GTPase Rheb. 5 Rheb directly binds to mTORC1 and regulates its activity in a GTP-dependent manner. 6 Thus, TSC2 inhibits Rheb-dependent activation of mTORC1. Phosphorylation and inactivation of TSC2 has first been shown to occur via PI3K/Akt. 7 Subsequently, several groups have shown that the Ras/ERK pathway also converges on the TSC1/2 complex. Ras-activated ERK1/2 directly phosphorylates TSC2 at sites different than Akt, resulting in TSC2 inactivation. 8 The downstream effector of ERK, RSK, also phosphorylates TSC2 at a unique site, thus inactivating it. 9 Therefore, TSC2 serves as a convergence point for multiple signaling inputs to mTORC1.Activation of S6K1. S6K1 is one of the best-characterized downstream targets of mTORC1, and rapamycin treatment re...

show abstract

Comprehensive copy number and gene expression profiling of the 17q23 amplicon in human breast cancer

Cited by 204 publications

References 35 publications

Mammary tumors in mice conditionally mutant for Brca1 exhibit gross genomic instability and centrosome amplification yet display a recurring distribution of genomic imbalances that is similar to human breast cancer

Mammary tumors in mice conditionally mutant for Brca1 exhibit gross genomic instability and centrosome amplification yet display a recurring distribution of genomic imbalances that is similar to human breast cancer

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

The role of S6K1 in ER-positive breast cancer

Contact Info

Product

Resources

About