Mutation and accumulation of p53 related to results of adjuvant therapy of postmenopausal breast cancer patients

Askmalm, Marie Stenmark; Carstensen, John; Nordenskjöld, Bo; Olsson, Birgit; Rutqvist, Lars Erik; Skoog, Lambert; Stål, Olle

doi:10.1080/02841860410029474

Cited by 18 publications

(10 citation statements)

References 38 publications

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“…Amplification analysis DNA was previously extracted from primary tumors (Askmalm et al, 2004). Analysis of the CCND1 and PAK1 genes were successfully performed in 224 and 214 samples, respectively.…”

Section: Patientsmentioning

confidence: 99%

Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer

et al. 2007

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The 11q13 region is amplified in approximately 15% of all breast tumors. Situated in this region are the cyclin D1 gene (CCND1) and the p-21-activated kinase 1 (PAK1) gene. Both genes encode proteins shown to activate the estrogen receptor (ER), leading to transcription of CCND1 and other ER-responsive genes. Here, we investigate the prognostic and treatment predictive role of CCND1 and PAK1 gene amplification in postmenopausal breast cancer patients randomized to tamoxifen treatment or no adjuvant treatment. Amplification of CCND1 and PAK1, assessed by real-time PCR, was observed in 12.5 and 9.3%, respectively. Amplification of PAK1 was seen in 37% of the CCND1-amplified tumors, indicating coamplification (Po0.001). In ER-positive patients, amplification of at least one of the genes indicated a reduced recurrence-free survival (P=0.025). When response to tamoxifen treatment was analysed, patients with PAK1 amplification showed decreased benefit from the drug (ER+; relative risk ratio (RR)=1.62; 95% confidence interval (CI), 0.47-5.55) compared to patients without amplification (ER+; RR=0.53; 95% CI, 0.32-0.88). This was not evident for CCND1 amplification. We show that PAK1 may be a predictor of tamoxifen resistance and furthermore, we do not discard PAK1 as a potential candidate oncogene in the 11q13 amplicon. In addition, we show that high pak1 protein levels may predict tamoxifen insensitivity.

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Section: Patientsmentioning

confidence: 99%

Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer

et al. 2007

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“…Askmalm et al have examined p53 alterations in 266 mainly node positive patients randomized to CMF or radiotherapy. A significant reduction in LRR probability after radiotherapy as compared with CMF was found in the group of patients without p53 alterations, whereas no benefit from radiotherapy was found for the group of patients showing p53 alterations [6]. One of the first cell death-regulating genes to be identified was BCL2, an anti-apoptotic gene that among others appears to block a distal step in the p53 pathway crucial to apoptosis.…”

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confidence: 98%

Impact of BCL2 and p53 on postmastectomy radiotherapy response in high-risk breast cancer. A subgroup analysis of DBCG82 b&c

et al. 2008

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“…Extraction of genomic DNA was performed as described before [30] and DNA concentration was estimated using a NanoDrop ND-1000 Spectrophotometer (NanoDrop Technologies). For mRNA preparation, fresh frozen tumor tissue was homogenized with a microdismembrator (B Braun) and total RNA was isolated using the mirVanaTM miRNA Isolation kit (Ambion), according to manufacturer's recommendations.…”

Section: Dna and Mrna Preparationmentioning

confidence: 99%

Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer

Pérez-Tenorio

Karlsson

Waltersson

et al. 2010

Breast Cancer Res Treat

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Aim: The Mammalian Target of Rapamycin (mTOR) and its substrates S6K1 and S6K2 regulate cell growth, proliferation and metabolism through translational control. RPS6KB1 (S6K1) and RPS6KB2 (S6K2) are situated in the commonly amplified 17q21-23 and 11q13regions. S6K1 amplification and protein overexpression have earlier been associated with a worse outcome in breast cancer, but information regarding S6K2 is scarce. The aim of this study was to evaluate the prognostic and treatment predictive relevance of S6K1/S6K2 gene amplification, as well as S6K2 protein expression in breast cancer. Results: S6K1 amplification/gain was detected in 10.7%/21.4% and S6K2 amplification/gain in 4.3%/21.3% of the tumors. S6K2 protein was detected in the nucleus (38%) and cytoplasm (76%) of the tumor cells. S6K1 amplification was significantly associated with HER2 gene amplification and protein expression. S6K2 amplification correlated significantly with high S6K2 mRNA levels, ER+ status and CCND1 amplification. S6K1 and S6K2 gene amplification was associated with a worse prognosis independent of HER2 and CCND1. S6K2 gain and nuclear S6K2 expression was related to an improved benefit from tamoxifen among patients with ER+ respectively ER+/PgR+ tumors. In the ER+/PgR-subgroup, nuclear S6K2 rather indicated decreased tamoxifen responsiveness. S6K1 amplification predicted reduced benefit from radiotherapy.Conclusions: This is the first study showing that S6K2 amplification and overexpression, like S6K1 amplification, have prognostic and treatment predictive significance in breast cancer.

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Mutation and accumulation of p53 related to results of adjuvant therapy of postmenopausal breast cancer patients

Cited by 18 publications

References 38 publications

Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer

Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer

Impact of BCL2 and p53 on postmastectomy radiotherapy response in high-risk breast cancer. A subgroup analysis of DBCG82 b&c

Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer

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