Breast cancer cells with acquired antiestrogen resistance are sensitized to cisplatin-induced cell death

Yde, Christina Westmose; Gyrd‐Hansen, Mads; Lykkesfeldt, Annè E.; Issinger, Olaf‐Georg; Stenvang, Jan

doi:10.1158/1535-7163.mct-07-0072

Cited by 25 publications

(20 citation statements)

References 38 publications

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“…These observations were similar to those reported by Yde et al (29): MCF-7-derived anti-estrogen-resistant cells were more sensitive to cisplatin-induced cell death than the parental cells. The results from this study suggest that treatment with cisplatin or TRAIL alone induced cell death in 30-50% of Tam-resistant cells, however, the maximum effect is evident when these cells are treated with cisplatin plus TRAIL.…”

Section: Discussionsupporting

confidence: 92%

Anti-estrogen-resistant breast cancer cells are sensitive to cisplatin plus TRAIL treatment

Rishi

Reddy

2015

Oncology Reports

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Abstract. Breast cancer patients who are positive for estrogen receptor (ER) are usually treated with anti-estrogen drugs, such as tamoxifen (Tam). However, a great majority of such patients eventually develop resistance to Tam. In this study, MCF-7 cells (with de novo and/or acquired resistance to Tam) as well as T47D cells (acquired resistance to Tam) models were used to investigate the effect of treatment with cisplatin plus tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The results in the two cell types treated with cisplatin plus TRAIL showed significantly increased cell death compared to that in the untreated control cells. A similar treatment had a minimal effect on normal breast cells, the increased cell death appeared to be caused by the activation of caspases and, inhibition of the activity of caspases (using relatively specific inhibitors) reduced the cell death caused by cisplatin plus TRAIL treatment. Taken together, the results suggested that cisplatin plus TRAIL treatment has the potential to provide a novel treatment strategy to improve the treatment outcome in anti-estrogen-resistant breast cancer patients. IntroductionHormonal influence on breast tissue and in breast cancer development has long been recognized. Examinations of ~70% of breast cancer patients have been found to be positive for estrogen receptor (ER)/progesterone (PR) receptor (1,2). Additionally, the receptor status has been used as a biomarker for therapy and prognosis. Currently, ER/PR + breast cancer patients are treated with anti-estrogen drugs, such as tamoxifen (Tam) or aromatase inhibitors (AIs) (3,4). Tam binds to ER, thereby preventing the binding of estrogen and subsequent activation of ER. Aromatase inhibitors (AI) suppress the activity of aromatase enzyme and thus, the production of estrogen. Although these inhibitors were shown to be effective, some patients develop resistance and do not respond to Tam therapy or other targeted endocrine therapies. The de novo resistance appears to be due to the up-regulation/overexpression of the HER2 receptor and/or Akt protein. Clinical and in vitro studies have also suggested that overexpression of the HER2 receptor is associated with resistance to hormone therapy (5-7). In addition, the majority of breast cancer patients with ER expression initially respond to endocrine therapy but, develop 'acquired' resistance over a period of time (8). MCF-7 and T47D breast cancer cell lines have been used as experimental models to investigate the mechanism(s) involved in acquired resistance to Tam (5,9,10). The results from such studies reported by our and other research groups have shown that drug resistance in these cells can be acquired through various mechanisms, including: i) loss of ERα expression, ii) altered activity of co-regulators, iii) cross-talk between the ERα and growth factor signaling pathways and, iv) overexpression of PKCα or PKCδ (3,5,11). These anti-estrogen-resistant models are also useful for the identification of other 'potential' therapeutic agents ...

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Section: Discussionsupporting

confidence: 92%

Anti-estrogen-resistant breast cancer cells are sensitive to cisplatin plus TRAIL treatment

Rishi

Reddy

2015

Oncology Reports

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“…Increased levels of PKCα correlate to and can induce tamoxifen [38,39] and multidrug [9,10] resistance of ER-positive cell lines. In addition, overexpression of PKCα in MCF-7 cells leads to increased proliferation which is in line with our tumor data [4], but also make them more susceptible to apoptotic insults [40,41]. We found that the cell line with no detectable PKCα expression, T47D, had a lower percentage of Ki-67-positive cells and slower growth rate than the other cell lines, similar to the tumor data.…”

Section: Discussionsupporting

confidence: 90%

PKCα expression is a marker for breast cancer aggressiveness

et al. 2010

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BackgroundProtein kinase C (PKC) isoforms are potential targets for breast cancer therapy. This study was designed to evaluate which PKC isoforms might be optimal targets for different breast cancer subtypes.ResultsIn two cohorts of primary breast cancers, PKCα levels correlated to estrogen and progesterone receptor negativity, tumor grade, and proliferative activity, whereas PKCδ and PKCε did not correlate to clinicopathological parameters. Patients with PKCα-positive tumors showed poorer survival than patients with PKCα-negative tumors independently of other factors. Cell line studies demonstrated that PKCα levels are high in MDA-MB-231 and absent in T47D cells which proliferated slower than other cell lines. Furthermore, PKCα silencing reduced proliferation of MDA-MB-231 cells. PKCα inhibition or downregulation also reduced cell migration in vitro.ConclusionsPKCα is a marker for poor prognosis of breast cancer and correlates to and is important for cell functions associated with breast cancer progression.

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“…Many of these deaths are due to chemo-resistance, which is a common problem in the treatment of BrCa [12,13]. Cisplatin and its analogues have been widely used for treatment of human cancers, including advanced BrCa [14-16]. However, resistance to cisplatin represents a major obstacle in the effective management of metastatic BrCa [17].…”

Section: Discussionmentioning

confidence: 99%

CCR9-CCL25 interactions promote cisplatin resistance in breast cancer cell through Akt activation in a PI3K-dependent and FAK-independent fashion

et al. 2011

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BackgroundChemotherapy heavily relies on apoptosis to kill breast cancer (BrCa) cells. Many breast tumors respond to chemotherapy, but cells that survive this initial response gain resistance to subsequent treatments. This leads to aggressive cell variants with an enhanced ability to migrate, invade and survive at secondary sites. Metastasis and chemoresistance are responsible for most cancer-related deaths; hence, therapies designed to minimize both are greatly needed. We have recently shown that CCR9-CCL25 interactions promote BrCa cell migration and invasion, while others have shown that this axis play important role in T cell survival. In this study we have shown potential role of CCR9-CCL25 axis in breast cancer cell survival and therapeutic efficacy of cisplatin.MethodsBromodeoxyuridine (BrdU) incorporation, Vybrant apoptosis and TUNEL assays were performed to ascertain the role of CCR9-CCL25 axis in cisplatin-induced apoptosis of BrCa cells. Fast Activated Cell-based ELISA (FACE) assay was used to quantify In situ activation of PI3Kp85, AktSer473, GSK-3βSer9 and FKHRThr24 in breast cancer cells with or without cisplatin treatment in presence or absence of CCL25.ResultsCCR9-CCL25 axis provides survival advantage to BrCa cells and inhibits cisplatin-induced apoptosis in a PI3K-dependent and focal adhesion kinase (FAK)-independent fashion. Furthermore, CCR9-CCL25 axis activates cell-survival signals through Akt and subsequent glycogen synthase kinase-3 beta (GSK-3β) and forkhead in human rhabdomyosarcoma (FKHR) inactivation. These results show that CCR9-CCL25 axis play important role in BrCa cell survival and low chemotherapeutic efficacy of cisplatin primarily through PI3K/Akt dependent fashion.

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Breast cancer cells with acquired antiestrogen resistance are sensitized to cisplatin-induced cell death

Cited by 25 publications

References 38 publications

Anti-estrogen-resistant breast cancer cells are sensitive to cisplatin plus TRAIL treatment

Anti-estrogen-resistant breast cancer cells are sensitive to cisplatin plus TRAIL treatment

PKCα expression is a marker for breast cancer aggressiveness

CCR9-CCL25 interactions promote cisplatin resistance in breast cancer cell through Akt activation in a PI3K-dependent and FAK-independent fashion

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