BACKGROUND:Cell culture studies have disclosed that the mitotic Aurora kinase A is causally involved in both tamoxifen and aromatase inhibitor resistant cell growth and thus may be a potential new marker for endocrine resistance in the clinical setting.MATERIAL AND METHODS:Archival tumor tissue was available from 1323 Danish patients with estrogen receptor (ER) positive primary breast cancer, who participated in the Breast International Group (BIG) 1-98 trial, comparing treatment with tamoxifen and letrozole and both in a sequence. The expression of Aurora A was determined by immunohistochemistry in 980 tumors and semi quantitively scored into three groups; negative/weak, moderate and high. The Aurora A expression levels were compared to other clinico-pathological parameters and outcome, defined as disease-free survival (DFS) and overall survival (OS).RESULTS:High expression of Aurora A was found in 26.9% of patients and moderate in 57.0%. High expression was significantly associated with high malignancy grade and HER2 amplification. High Aurora A expression was significantly more frequent in ductal compared to lobular carcinomas. We found no significant association between Aurora A expression and DFS or OS and no evidence of interaction between Aurora A expression and benefits from tamoxifen versus letrozole.CONCLUSIONS:Aurora A expression in breast tumors was associated with high malignancy grade III and with HER2 amplification. A trend as a prognostic factor for OS was found in patients with high Aurora A expression. No predictive property was observed in this study with early breast cancer.

Objectives: Laser lead extraction in patients with multiple- or old implantable cardioverter defibrillator (ICD) leads is challenging. Following renewed guidelines the number of implanted ICD/CRT devices has been rising in recent years. In the same way the number of ICD leads that need to be extracted is emerging. Single- as well as dual coil leads are frequently used. As adhesions are very common at the side of the shock coils, we investigated success- and procedural complication rates of laser lead extraction procedures in single versus dual coil leads.

In this study, T47D cell lines resistant to the antiestrogen fulvestrant were established and analyzed to explore, whether a switch to HER signaling, as seen in fulvestrant resistant MCF-7 cell lines, is a general resistance mechanism. We find that parental T47D cells depend on ER and HER signaling for growth. Fulvestrant resistant T47D cells have lost ER expression and, although HER2 was over expressed, growth was only partially driven by HER receptors. Instead c-Src was important for resistant growth. Thus, the T47D and MCF-7 model system unravel different resistance mechanisms which may be important for fulvestrant resistant breast cancer patients.

Objectives: Laser lead extraction due to infection of the pacing system or malfunction of the lead itself is the treatment of choice, especially for those that have been implanted for several years. If continuous pacing is mandatory new leads need to be implanted. Multiple lead devices incline to cause stenotic lesions or complete occlusion of the subclavian vein thereby complicating lead implantation.

Abstract To study the mechanisms behind treatment resistance, we have previously established a large panel of antiestrogen resistant breast cancer cell lines based on the estrogen receptor (ER)-positive breast cancer cell line, MCF-7. It seems to be a general phenomenon that MCF-7 cells switch from ER driven to human epidermal growth factor receptor (HER) driven cell growth upon development of fulvestrant resistance. To obtain a broader knowledge of the resistance mechanisms, we have established four fulvestrant resistant subclones from the ER-positive breast cancer cell line, T47D. The parental T47D cells were confirmed to be estrogen responsive and short-term treatment of the parental T47D cells with fulvestrant severely reduced cell growth as well as protein expression of ER and the estrogen regulated proteins, insulin-like growth factor 1 receptor alpha (IGF-1Rα) and progesterone receptor (PR). All four fulvestrant resistant cell lines had reduced mRNA and protein expression of HER1 and HER4 compared to T47D, while HER2 was highly up regulated in the fulvestrant resistant cell lines and ER was lost. No difference in response to the HER2 inhibitor trastuzumab or the specific HER2 kinase inhibitor AG825 was observed between the fulvestrant resistant cell lines and T47D, indicating that HER2 is not the main driver of fulvestrant resistance in T47D cells. We found no indication of involvement of the two classical signaling pathways downstream of the HER receptors (Ras/Raf/Erk and PI3K/Akt). However, the JNK inhibitor SP600125 preferentially inhibited growth of two tested fulvestrant resistant cell lines. Withdrawal of fulvestrant for several weeks did not result in regain of ER expression, or in change of HER receptor expression, supporting a stable resistant phenotype. In conclusion, loss of ER expression explains the lack of effect of fulvestrant in the T47D fulvestrant resistant cell lines. Noteworthy, the observed over expression of HER2 in the fulvestrant resistant T47D cells does not seem to be the main driver of cell growth, as HER2 targeted therapies like trastuzumab and HER2 kinase inhibitor did not exert a preferential growth inhibition of resistant cells. These breast cancer cells with high endogenous HER2 expression will be used as a model mimicking HER2 positive breast cancer which does not respond to standard HER2 targeted therapies. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-18.

Objective: Pacemaker or ICD lead removal without technical support is impossible in patients with lead dysfunction more than ten years after lead implantation. Mechanical lead extraction in these patients carries a risk for major bleeding complications. In this retrospective analysis we analysed the risk of laser lead extraction using the excimer laser in patients with >10 yo leads.

The expression of CYP1A1 and CYP1B1, encoding enzymes known to play a central role in oxidative metabolism of a wide range of compounds including steroids, was significantly increased in anti‐estrogen–resistant human breast cancer cell lines. This was a purely regulatory phenomenon because no gene amplification had occurred. In anti‐estrogen–sensitive MCF‐7 cells, the steroidal anti‐estrogen, ICI 182780, is able to induce the expression of the arylhydrocarbon receptor (AhR)‐regulated gene product, CYP1A1, via an estrogen receptor (ER)‐ mediated process. This observation suggests cross‐talk between the AhR and ER systems. Surprisingly, the increased constitutive expression in anti‐estrogen–resistant cells of CYP1A1 and CYP1B1 mRNAs, encoding detoxification enzymes, had no effect on the activity of the ICI 182780 compound. The ICI 182780 regulation of estradiol‐inducible genes was found to be identical in the resistant and sensitive breast cancer cell lines. In conclusion, anti‐estrogen resistance is not due to conversion of ICI 182780 to less active compounds. Int. J. Cancer 88:902–906, 2000. © 2000 Wiley‐Liss, Inc.

Development of resistance to tamoxifen is a serious problem in treatment of breast cancer patients. Although the mechanisms for development of resistance are unclear, an altered expression of alternatively spliced estrogen receptor (ER) mRNA has been suggested to be involved. We have looked for differential expression of ER splice variants lacking exon 2 (ERdeltaE2), exon 3 (ERdeltaE3), exon 4 (ERdeltaE4), exon 5 (ERdeltaE5), exon 7 (ERdeltaE7), and exons 4 and 7 (ERdeltaE4, 7) in the human breast cancer cell line MCF-7 and 10 ER-positive MCF-7 sublines resistant to the antiestrogens tamoxifen, ICI 164,384 or ICI 182,780. No major differences in the expression were demonstrated between MCF-7 cells and resistant cells, indicating that ER splice variants are not involved in antiestrogen resistance in this model system. Furthermore, despite a high mRNA level of some of the ER splice variants, no corresponding proteins could be detected using Western blot analysis.

Breast cancer patients with an estrogen receptor (ER) positive tumor can be treated with the anti-estrogen tamoxifen, but development of anti-estrogen resistance is a serious problem. We have analyzed a tamoxifen resistant human breast cancer cell line MCF-7/TAMR-1 for alterations in ER which might explain the tamoxifen resistance. The MCF-7/TAMR-1 cells expressed both wildtype ER mRNA and protein, and by RT-PCR we were able to clone ER cDNAs corresponding to the following mRNA splice variants: ERΔE2, ERΔE4, ERΔE5, ERΔE7 and a new double splice variant lacking both exon 4 and 7 (ERΔE4,7). The existence of the ERΔE4,7 variant was confirmed by RNase protection assay. Semi-quantitative RT-PCR revealed that ERΔE2 mRNA was expressed at a higher level in MCF-7/TAMR-1 cells, whereas the ERΔE5 mRNA was expressed at a significantly lower level in MCF-7/TAMR-1 cells compared with MCF-7 cells. The differential expression of the two ER mRNA splice variants indicates that they may be involved in anti-estrogen resistance, although the present knowledge of their biological function does not provide us with an explanation.