A mechanism of drug resistance to tamoxifen in breast cancer

Schafer, Jennifer Mac Gregor; Bentrem, David J.; Takei, Hiroyuki; Gajdos, Csaba; Badve, Sunil; Jordan, V. Craig

doi:10.1016/s0960-0760(02)00251-0

Cited by 31 publications

(20 citation statements)

References 19 publications

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“…The development of hormone resistance is also an important factor in breast cancer progression against endocrine therapy. Increased EGFR or HER-2 activity may lead to resistance against tamoxifen, a selective estrogen receptor modulator (Schafer et al, 2002). Capsaicin, which we showed to modulate the EGFR/HER-2 pathway including activated ERK, cyclin D1 and p27…”

Section: Discussionmentioning

confidence: 69%

Capsaicin causes cell-cycle arrest and apoptosis in ER-positive and -negative breast cancer cells by modulating the EGFR/HER-2 pathway

et al. 2009

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Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is an ingredient of chili peppers with inhibitory effects against cancer cells of different origin. We examined the activity of capsaicin on breast cancer cells in vitro and in vivo. The drug potently inhibited growth of ER-positive (MCF-7, T47D, BT-474) and ER-negative (SKBR-3, MDA-MB231) breast cancer cell lines, which was associated with G 0 /G 1 cell-cycle arrest, increased levels of apoptosis and reduced protein expression of human epidermal growth factor receptor (EGFR), HER-2, activated extracellular-regulated kinase (ERK) and cyclin D1. In contrast, cell-cycle regulator p27 KIP1, caspase activity as well as poly-ADP ribose polymerase (PARP) cleavage were increased. Notably, capsaicin blocked breast cancer cell migration in vitro and decreased by 50% the size of MDA-MB231 breast cancer tumors growing orthotopically in immunodeficient mice without noticeable drug side effects. in vivo activation of ERK was clearly decreased, as well as expression of HER-2 and cyclin D1, whereas caspase activity and PARP cleavage products were increased in tumors of drug-treated mice. Besides, capsaicin potently inhibited the development of preneoplastic breast lesions by up to 80% without evidence of toxicity. Our data indicate that capsaicin is a novel modulator of the EGFR/HER-2 pathway in both ERpositive and -negative breast cancer cells with a potential role in the treatment and prevention of human breast cancer.

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Section: Discussionmentioning

confidence: 69%

Capsaicin causes cell-cycle arrest and apoptosis in ER-positive and -negative breast cancer cells by modulating the EGFR/HER-2 pathway

et al. 2009

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“…We have developed methods to detect dual immunofluorescence of Ki-67 and TUNEL (adapted from Schafer and colleagues; ref. 26) in paraffin-embedded tissues that will allow simultaneous evaluation of the patterns of proliferation and apoptosis in situ. Five-micrometer sections from each tumor were baked in a 60jC oven for 30 min, dewaxed in xylene, and rehydrated through graded alcohols.…”

Section: Methodsmentioning

confidence: 99%

“…Assuming equal sample sizes and a two-sample Student's t test, we estimated that eight mice per group were needed to have 80% power (with a type 1 error of 5%) to detect a difference of 60% in mean volume between groups. In our first experiment, we started with 14 animals per group with planned animal sacrifice at different time points for biochemical analysis so that (26). We modified this assay to use as a screen for novel therapies and showed that it could be used as a surrogate to discriminate between normal and malignant tissue response to h 1 integrin inhibitory antibody in vivo (19).…”

Section: Methodsmentioning

confidence: 99%

β1 Integrin Inhibition Dramatically Enhances Radiotherapy Efficacy in Human Breast Cancer Xenografts

et al. 2008

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B 1 Integrin signaling has been shown to mediate cellular resistance to apoptosis after exposure to ionizing radiation (IR). Other signaling molecules that increase resistance include Akt, which promotes cell survival downstream of B 1 integrin signaling. We previously showed that B 1 integrin inhibitory antibodies (e.g., AIIB2) enhance apoptosis and decrease growth in human breast cancer cells in threedimensional laminin-rich extracellular matrix (lrECM) cultures and in vivo. Here, we asked whether AIIB2 could synergize with IR to modify Akt-mediated IR resistance. We used three-dimensional lrECM cultures to test the optimal combination of AIIB2 with IR treatment of two breast cancer cell lines, MCF-7 and HMT3522-T4-2, as well as T4-2 myr-Akt breast cancer colonies or HMT3522-S-1, which form normal organotypic structures in three-dimensional lrECM. Colonies were assayed for apoptosis and B 1 integrin/Akt signaling pathways were evaluated using Western blot. In addition, mice bearing MCF-7 xenografts were used to validate the findings in three-dimensional lrECM. We report that AIIB2 increased apoptosis optimally post-IR by down-regulating Akt in breast cancer colonies in three-dimensional lrECM. In vivo, addition of AIIB2 after IR significantly enhanced tumor growth inhibition and apoptosis compared with either treatment alone. Remarkably, the degree of tumor growth inhibition using AIIB2 plus 2 Gy radiation was similar to that of 8 Gy alone. We previously showed that AIIB2 had no discernible toxicity in mice; here, its addition allowed for a significant reduction in the IR dose that was necessary to achieve comparable growth inhibition and apoptosis in breast cancer xenografts in vivo. [Cancer Res 2008;68(11):4398-405]

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“…Drug resistance is a major clinical limitation for the successful management of breast cancers (42)(43)(44)(45). In the present study, we investigated the mechanisms of TAM-induced apoptosis and drug resistance using MCF-7 cells and its multidrug-resistant variant, MCF-7/ADR cells.…”

Section: Role Of Pkc-erk Signaling In Tamoxifen-induced Apoptosis Andmentioning

confidence: 99%

Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells

Xie

2012

Oncol Rep

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Abstract. This study was designed to investigate the role of protein kinase C (PKC) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in tamoxifen (TAM)-induced apoptosis and drug resistance in human breast cancer cells. Drug-sensitive, or estrogen receptor (ER)-positive human breast carcinoma cells (MCF-7) and the multi-drug-resistant variant (ER-negative) MCF-7/ADR cells were treated with doses of TAM for various periods of time. Cell viability and apoptosis were assessed using cell counting, DNA fragmentation and flow cytometric analysis. We found that TAM administration caused a significant increase in apoptosis of MCF-7 cells but not MCF-7/ADR cells. Western blot analysis revealed enhanced expression of PKCδ but decreased expression of PKCα in ER-positive MCF-7 cells; while ER-negative MCF-7/ADR cells had decreased levels of PKCδ and increased levels of PKCα. Interestingly, we observed that in MCF-7 cells, TAM stimulated apoptosis by promoting rapid activation of PKCδ, antagonizing downstream signaling of ERK phosphorylation; while in MCF-7/ADR cells, TAM upregulated PKCα, which promoted ERK phosphorylation. These results suggest that PKCδ enhances apoptosis in TAM-treated MCF-7 cells by antagonizing ERK phosphorylation; while the PKCα pathway plays an important role in TAM-induced drug resistance by activating ERK signaling in MCF-7/ADR cells. The combination of TAM with PKCα and ERK inhibitors could promote TAM-induced apoptosis in breast cancer cells. IntroductionBreast cancer is a common malignancy in females and the second cause of death from cancer in women today (1). Treatment for breast cancer includes surgery, chemotherapy, radiotherapy and endocrine therapy. Tamoxifen (TAM), an antagonist of the estrogen receptor (ER), is a selective ER modulator (SERM). TAM is a front-line endocrine therapeutic drug for ER-positive breast cancers. Results from TAM therapy showed a 40-50% reduction in the risk of cancer recurrence and cancer mortality (2). Recently, TAM has been demonstrated to be effective for some ER-negative breast cancers, as well as other types of cancers, including gliomas. These data suggest that TAM may also be implicated in ER-independent antitumor mechanisms (3,4). Of note, some advanced breast cancers that initially respond well to TAM eventually become refractory to treatment (5-9). Thus, the traditional mechanism of TAM action through the ER is challenged, and other noncanonical pathways need to be explored.Protein kinase C (PKC), a family of serine/threonine kinases, is involved in many important cellular functions, including cell proliferation, migration, differentiation, and apoptosis (10-12). Twelve PKC isoforms have been discovered in various cell types, including conventional PKCs (cPKCα, βI/βII and γ), novel PKCs (nPKCδ, ε, η), and atypical PKCs (aPKCζ) (13,14). The expression of PKCα, δ, ε, η, γ, μ, and ζ has been detected in MCF-7 cells (15,16); PKCα is a marker for anti-estrogen resistance and is involved in the growth of TAM-resistant human breast cancer cell...

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A mechanism of drug resistance to tamoxifen in breast cancer

Cited by 31 publications

References 19 publications

Capsaicin causes cell-cycle arrest and apoptosis in ER-positive and -negative breast cancer cells by modulating the EGFR/HER-2 pathway

Capsaicin causes cell-cycle arrest and apoptosis in ER-positive and -negative breast cancer cells by modulating the EGFR/HER-2 pathway

β1 Integrin Inhibition Dramatically Enhances Radiotherapy Efficacy in Human Breast Cancer Xenografts

Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells

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