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Detecting signals in the mammalian target of rapamycin (mTOR), and the estrogen receptor (ER) pathways for prediction of treatment response may be a future clinical tool in primary breast cancer. Here, we investigated the validity and value of the mTOR targets p70-S6 kinase (S6K) 1 and 2 as biomarkers for tamoxifen sensitivity in vitro and in two independent tamoxifen randomized postmenopausal breast cancer cohorts. In addition, the prognostic value of the S6Ks was evaluated. We found S6K1 to correlate with HER2 and cytoplasmic Akt activity, whereas S6K2 and phosphorylated S6K were closer connected with ER positivity, low proliferation and nucleic p-Akt. Treatment prediction and prognosis were evaluated by immunohistochemical staining. Nuclear accumulation of S6K1 was indicative of a reduced tamoxifen treatment effect, compared with a significant benefit from tamoxifen treatment in patients without tumor S6K1 nuclear accumulation. Patients with a combination of S6K1 nuclear accumulation and S6K2 cytoplasmic accumulation in the tumor cells had no tamoxifen benefit. Also, S6K1 and S6K2 activation, indicated by p-S6K-t389 expression, was associated with low benefit from tamoxifen compared with untreated patients. In addition, high protein expression of S6K1, independent of localization, predicted worse prognosis. This was not evident for variations in S6K2 or p-S6K-t389 expression. In conclusion, the mTOR targeted kinases S6K1 and S6K2 interfere with proliferation and response to tamoxifen. Monitoring their activity and intracellular localization may provide biomarkers for breast cancer treatment, allowing for identification of a group of patients less likely to benefit from tamoxifen and thus in need of an alternative or additional treatment. Citation Format: Josefine Bostner, Elin Karlsson, Cecilia Bivik, Gizeh Perez-Tenorio, Tommy Fornander, Olle Stål. S6 kinase signaling in prognosis and tamoxifen response in two randomized breast cancer cohorts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3295. doi:10.1158/1538-7445.AM2014-3295

The majority of all cancer deaths are caused by metastases rather than the primary tumour. The process by which cells can develop migratory properties is suggested to occur through an epithelial-mesenchymal transition (EMT). The microRNA (miR) 200 family have been associated with EMT and acts negatively on ZEB1 which is a repressor of CDH1 (E-cadherin) thereby supports the epithelial maintenance. Our aim was to investigate the expression of the EMT markers ZEB1, CDH1, miR-200c and miR141 in metastatic colorectal cancer and primary breast tumours and to explore their prognostic significance as well as their correlations to clinicopathological factors. Matched tissue from primary tumour and liver metastasis of 10 colorectal cancer patients and another 15 tissues from CR liver metastasis were used in this study. Moreover, primary tumours from 90 stage II breast tumours from postmenopausal patients, randomized to radiotherapy vs chemotherapy as well as tamoxifen or no endocrine treatment, were included. microRNA and gene expression was studied by quantitative real-time PCR. Correlations between the mir-200 family and CDH1 and inverse correlations to ZEB were found in 15 CR liver metastases as well as in the breast cancer material. In the breast cancer material the gene expression of CDH1 was confirmed by positive correlation to CNV of the CDH1 gene. In the liver metastases low CDH1 was associated with recurrence. A reduction in the mir-200 family was seen in matched normal CR mucosas, primary CRC tumours and liver metastasis and lower expression was found in metastatic CRC primary tumours compared to non-metastatic. In the breast cancer material, wild-type p53 was associated with high expression of the miR cluster which is in agreement with recently presented data of p53 as a suggested regulator of the EMT pathway, via the miR-200 family. In addition, low miR-141/200 expression was associated with activation of the PI3K/AKT pathway, especially in combination with a wild-type p53. miR-141 correlated with positive oestrogen receptor (ER) status, whereas miR200c negatively correlated with HER2 status, suggesting that these miRs may play different roles in different subtypes of breast cancer. A low expression of the miR cluster was associated with a worse outcome in terms of a decreased distant recurrence-free survival. In addition, the levels of miR141/200c were associated with the response to radiation and chemotherapy. Among patients carrying tumours with low miR-141/200c expression, chemotherapy significantly reduced the risk of distant metastases, whereas a high expression of miR141/200c predicted good benefit from radiation, using local or distant recurrence-free survival as an endpoint. These findings support the role of miR141/200c in metastatic progression, and indicate that these markers of EMT could be useful prognostic and treatment predictive factors in cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 451. doi:1538-7445.AM2012-451

Amplification in the 11q13 region has been found in around 15% of all breast cancers and is strongly correlated with oestrogen receptor (ER) positive tumours. We have previously found that amplification of at least one of the genes PAK1 or CCND1 is associated with decreased recurrence-free survival among ER+ patients. Other genes in the amplicon might also contribute to this effect and situated close to CCND1 are the FGF-3, -4 and -19 genes. The FGF-4 protein has been shown to inhibit the expression of the ER a regulator miR-206 in chicken embryo. In this study we analysed 23 tumours with and 27 tumours without previously detected 11q13 amplification to explore if 11q13 amplification is associated with decreased levels of miR-206 and if miR-206 is associated with ER expression. Using eal-time PCR, we found that miR-206 expression was inversely correlated to CCND1 and 11q13 amplification (P=0.016 and P=0.022 respectively). Tumours with low miR-206 expression had higher levels of ER a than tumours with intermediate and high expression (P=0.043). In vitro studies of the breast cancer cell lines SKBR3 and ZR751 showed that treatment with FGF-3, -4 or -19 lowered the expression of miR-206. We conclude that miR-206 might be an important regulator of ER a expression. Our results that low mir-206 is associated with CCND1 amplification and thereby also FGF-4 amplification in combination with the findings that FGF-3, -4, and -19 may regulate the expression of miR-206 in vitro points towards the possibility of a miR-206 regulator, FGF-4 or another FGF, present in the amplicon. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1127.