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

Abstract

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

242 Phosphorylated P70S6K in noninvasive low grade urothelial carcinoma of the bladder: Correlation with tumor recurrence

“…(c) LG-URCa with high p-p70S6K immunohistochemical staining exhibited a higher risk of recurrence (P < 0.05). 13,16 We demonstrated that p-4E-BP1 and p70S6K revealed a diverse pattern regarding their association with tumor recurrence. This finding suggests that p-4E-BP1 and p70S6K are not activated equally in the In our study, high p-p70S6K expression, as shown by the immunohistochemical staining, predicted recurrence for LG-URCa treated by transurethral resection, demonstrating that the mTOR signaling pathway thorough p-p70S6K is involved in LG-URCa recurrence.…”

The Р60-S6K1 isoform of ribosomal protein S6 kinase 1 is a product of alternative mRNA translation

“…In case of p60-S6K1 expressed in the p85 -/p70 -/ p60 + HEK-293 cells, the absence of the Thr-412/389 phosphorylation event arises intriguing questions about p60-S6K1 activity. If the activity of the major S6K1 isoforms is dependent on mTORC1-mediated S6K1 has been linked to the regulation of cell proliferation [32] and motility [33,34] that are affected in transformed cells and numerous data suggest implication of S6K1 in carcinogenesis [13][14][15][16][17][18][19][20][21].…”

“…Overexpression of the S6K1 gene and deregulated S6K1 signaling have been found in different malignancies, including breast, prostate, thyroid, brain and gastric cancers [13][14][15][16][17][18][19][20][21] that according to multiple studies correlate with poor prognosis of disease [14,[20][21][22]. However, implication of different S6K1 isoforms in carcinogenesis is poorly understood.…”

Preclinical validation of a novel compound targeting p70S6 kinase in breast cancer

“…The chromosomal region 17q23 containing the p70S6K gene (RPS6KB1) is amplified in approximately 10% of all primary breast cancer cases, leading to p70S6K overexpression [16][17][18][19] and this amplification is associated with poor prognosis [16,[20][21][22]. Interestingly, overexpression of p70S6K protein is linked to increased risk of locoregional recurrence in node-negative early breast cancer patients [20].…”

“…The chromosomal region 17q23 containing the p70S6K gene (RPS6KB1) is amplified in approximately 10% of all primary breast cancer cases, leading to p70S6K overexpression [16][17][18][19] and this amplification is associated with poor prognosis [16,[20][21][22]. Interestingly, overexpression of p70S6K protein is linked to increased risk of locoregional recurrence in node-negative early breast cancer patients [20]. Moreover, p70S6K is highly sensitive to signals coming from growth factors, amino acids, nutrients and hypoxia and relays these signals to regulate a vast list of substrates, eventually controlling many oncogenic processes, such as cell growth and proliferation, survival and apoptosis, autophagy, migration and invasion [1,23].…”