| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
B pathway and endocrine-resistant breast cancer
Buck Institute for Age Research, Novato, California 94945, USA
1 Stiftung Tumorbank Basel, Lörracherstrasse 50, CH-4125 Riehen, Switzerland
(Requests for offprints should be addressed to C C Benz, Cancer and Developmental Therapeutics Program, Buck Institute for Age Research, 8001 Redwood Blvd., Novato, CA 94945, USA; Email: cbenz{at}buckinstitute.org)
This paper was presented at the 1st Tenovus/AstraZeneca Workshop, Cardiff (2005). AstraZeneca has supported the publication of these proceedings.
 |
Abstract |
|---|
 Top Abstract Receptor crosstalk and endocrine...NF{kappa}B in organ development...Importance of NF{kappa}B in...NF{kappa}B inhibition can...Targeting the NF{kappa}B pathway...References |
|---|
B (NFB), a family of ubiquitously expressed transcription factors that for nearly two decades have been known to be critical regulators of mammalian immune and inflammatory responses, and more recently have been associated with chemotherapy resistance. With the demonstration that activation of NFB is absolutely required for normal mammary gland development, NFB involvment in human breast cancers was initially explored and linked to the development of hormone-independent (ER-negative) breast cancer. Newer clinical evidence now implicates NFB activation, particularly DNA-binding by the p50 subunit of NFB, as a potential prognostic marker capable of identifying a high-risk subset of ER-positive, primary breast cancers destined for early relapse despite adjuvant endocrine therapy with tamoxifen. Furthermore, initial preclinical studies suggest that treatment strategies designed to prevent or interrupt activation of NFB in cell-line models of these more aggressive, ER-positive breast cancers can restore their sensitivity to such standard endocrine agents as tamoxifen.
|
Receptor crosstalk and endocrine resistance |
|---|
|
TopAbstractReceptor crosstalk and endocrine...NF{kappa}B in organ development...Importance of NF{kappa}B in...NF{kappa}B inhibition can...Targeting the NF{kappa}B pathway...References |
|---|
Recent studies are beginning to elucidate how signaling pathways activated by ErbB-related membrane receptor tyrosine kinases (RTK) crosstalk with ER pathways (reviewed in Benz 2004a,b). Membrane receptor-initiated signaling through the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol-3-kinase (PI3K)-Akt pathway results in phosphorylation of ER on its various serine (S167, S118, S104, S106) residues and leads to both ligand-dependent and ligand-independent ER-mediated gene activation via ‘classical’ (direct ER DNA-binding at promoters containing estrogen-response elements) and ‘non-classical’ (ER tethering and coactivation of other DNA-bound transcription factor complexes such as AP-1, Sp1, C/EBPß and CREB) gene induction. Importantly, the net transcriptional effect of crosstalk that phosphorylates ER and its many transcriptional coregulators includes the functional conversion of an ER-binding antiestrogen such as tamoxifen into an ER agonist, capable of driving ER-positive cancer growth almost as efficiently as the potent estrogen, estradiol (Benz et al. 1992). Promising preclinical results from our well-characterized MCF-7/HER2 model of ER-positive/ErbB2-positive breast cancer are now fueling clinical studies involving patients with endocrine-resistant, ER-positive breast cancers, in which ErbB RTK inhibitors are being administered in combination with tamoxifen (Benz et al. 1992, Kurokawa et al. 2000, Shou et al. 2004, Schiff et al. 2004).
Alterations in ER crosstalk pathways clinically linked with tamoxifen resistance but not necessarily originating from ErbB2 amplification and overexpression have also been described; these include enhanced activation of the gene-regulating transcription factor complex, AP-1 (Johnston et al. 1999, Schiff et al. 2000), dysregulated PI3/Akt (Campbell et al. 2001), protein kinase C
(Chisamore et al. 2001), and the insulin-like growth factor I (Parisot et al. 1999) signaling pathways. Notably, all of these signaling pathways leading to tamoxifen resistance share a common mechanistic link with activation of another gene-regulating complex, nuclear factor-B (NFB) (Vertegaal et al. 2000, Zhou et al. 2000, Bhat-Nakshatri et al. 2002, DeGraffenried et al. 2004).
|
NFB in organ development and disease
|
|---|
|
TopAbstractReceptor crosstalk and endocrine...NF{kappa}B in organ development...Importance of NF{kappa}B in...NF{kappa}B inhibition can...Targeting the NF{kappa}B pathway...References |
|---|
B complex is composed of a family of inducible transcription factors found in almost all cells (Baeuerle & Baltimore 1996, Ghosh et al. 1998, Allen & Tresini 2000); and this complex is generally recognized as an essential cell mediator acting ‘at the crossroads of life and death’ (Karin & Lin 2002). Activation of NFB occurs in response to extra-cellular chemical stresses, various cytokines and growth stimuli, resulting in the direct induction of hundreds of genes whose cellular influences extend well beyond those of the immune system, where its essential role was first appreciated nearly two decades ago (Pahl 1999). In fact, the antiapoptotic, proliferation-, motility- and invasion-promoting roles of NFB appear to be critical for normal organ development, including the mammary gland (reviewed in Cao & Karin 2003). NFB activation can become abnormal during organ aging, with development and progression of various chronic inflammatory disorders, and in malignancies such as B and T cell lymphoma and leukemia, and thyroid, head and neck, gastrointestinal, and breast carcinoma (Baldwin 2001, Giardina & Hubbard 2002, Feinman et al. 2004, Veiby & Read 2004).
The NFB family consists of five mammalian members: p50 (NFB1), p52 (NFB2), p65 (relA), c-rel and relB. These all share a conserved 300-aminoacid N-terminal Rel homology domain (homologous to that encoded by the avian oncogene, v-Rel) that is responsible for dimerization, nuclear translocation, DNA binding, and association with IB inhibitory proteins (Dixit & Mak 2002, Ghosh & Karin 2002). These Rel family members exist as homo- or hetero-dimers, although the most abundant form of intra-cellular NFB is generally thought to be the p50/p65 heterodimer. In resting cells, NFB is cytoplasmically sequestered as a latent complex bound to one or more members of the IB protein family (IB, IBß, IB
, IB
, Bcl-3, and the precursor Rel proteins p100 and p105). Diverse cell stimuli (e.g. tumor necrosis factor (TNF), CD40 ligand, interleukin (IL)-1, TRANCE, epidermal growth factor (EGF), phorbol esters, peroxides, ionizing radiation) induce phosphorylation (via activation of the IB kinase complex, IKK) and subsequent proteasomal degradation of IB inhibitory proteins, activating NFB for nuclear translocation, where it binds promoter-specific B consensus DNA elements that direct transcription of over 180 known NFB target genes. While phosphorylation and degradation of IB inhibitory proteins are considered the rate-limiting if not obligate mechanisms by which NFB is activated, novel NFB phosphorylating kinases and IKK-independent pathways leading to IB proteasomal degradation have recently been described. Most activated forms of NFB induce gene transcription, although specific NFB subunits lack transactivation domains; thus, activation and nuclear translocation of p50/p50 and p52/p52 homodimers can result in repression of NFB-dependent genes (Ghosh & Karin 2002). However, when either NFB p50 or p52 products of the p105 and p100 Rel precursor proteins are bound to the oncogenic and noninhibitory IB family member, Bcl-3, they become transcriptionally competent and stimulate expression of NFB-dependent genes (Cogswell et al. 2000, Ghosh & Karin 2002).
Since NFB regulates so many known survival and proliferation genes, it is not surprising that NFB activation has generally been implicated in cancer chemotherapy resistance mechanisms (Wang et al. 1999). When first studied in human breast cancer cell lines and breast cancer samples, however, constitutive activation of NFB was associated only with hormone-independent (ER-negative) breast cancers, and this was thought to be due to its known inhibitory effects on almost all steroid receptors, including ER (Nakshatri et al. 1997).
|
Importance of NFB in hormone-dependent breast cancer
|
|---|
|
TopAbstractReceptor crosstalk and endocrine...NF{kappa}B in organ development...Importance of NF{kappa}B in...NF{kappa}B inhibition can...Targeting the NF{kappa}B pathway...References |
|---|
B activation was initially linked with the etiology and progression of hormone-independent breast cancers, where it was shown transcriptionally to induce genes mediating cell proliferation and invasion, such as cyclin D1 and urokinase-type plasminogen activator (uPA). Measured by DNA-binding, transactivation and immunoblot assays, NFB activation was first evaluated in several samples and cell lines, where it was found to be minimal in ER-positive breast cancers and cell lines but constitutively elevated in ER-negative breast cancers and cell lines (Nakshatri et al. 1997, Sovak et al. 1997). A subsequent study compared a small number of breast cancers with normal adjacent breast tissue (and also a few breast cancer cell lines) by measuring total NFB DNA-binding activity and subunit (p65, c-rel, p52 and p50) protein and transcript expression levels (Cogswell et al. 2000). The breast cancer samples all showed greater total NFB DNA-binding activity than the normal mammary gland tissue, but the increased tumor activity did not correlate with tumor ER status. In contrast, the cell line results again confirmed low NFB activation in ER-positive cell lines and high NFB activation in ER-negative breast cancer cells; moreover, these breast cancer cell lines showed predominantly increased p65 subunit expression and p65/p50 NFB DNA-binding activity, while the breast tumor samples showed selective upregulation of p50, p52 and c-rel expression (as well as Bcl-3) and increased DNA-binding by complexes composed mostly of these subunits and with relatively little p65 (Cogsell et al. 2000).
We recently performed the most extensive evaluation to date of NFB activation in primary human breast tumor samples in order to clarify the extent and clinical importance of NFB activation in hormone-dependent breast cancer (Zhou et al. 2005). With a new ELISA-based method to quantitate specific p65 and p50 NFB DNA-binding subunits, these subunit activities were independently measured in 81 ER-positive, primary breast cancer sample extracts with a wide range of ER content (group A samples:>100 fmol/ mg protein; group B samples: 21–87 fmol/mg protein). NFB p50 and p65 subunit DNA-binding activities were also evaluated for their prognostic association with clinical outcome in the subset of 59 group B cases that were comparably staged, characterized for a number of other prognostic biomarkers (Quong et al. 2002), uniformly treated with adjuvant tamoxifen, and clinically followed until metastatic relapse to determine disease-free patient survival (Zhou et al. 2005). Among the entire collection of 81 breast cancer samples (groups A+B), DNA-binding complexes with the p50 NFB subunit were almost twofold more abundant than those with the p65 NFB subunit, although these two independently measured parameters were tightly correlated (rs = 0.86, P < 0.0001). As illustrated in Fig. 1
(panel A), the group B breast cancers with a median under 0.5-fold lower ER content showed significantly higher NFB DNA-binding than the group A tumors with higher ER content, indicating that hormone-dependent breast cancers might be subset according to NFB activity and ER content. Metastatic relapse rates and disease-free survival (DFS) status were available only for the group B cases; despite uniform adjuvant treatment with tamoxifen, the 13/59 primary breast tumors destined for later relapse possessed significantly higher NFB p50 DNA-binding than the 46/59 similarly staged, ER-positive cases not destined for relapse. The generally lower NFB p65 DNA-binding activities followed a similar trend that did not reach statistical significance. Regression tree analyses were performed on both the p50 and p65 DNA-binding values to establish statistical cutpoints (0.95 and 0.75 respectively) that would optimally separate the Kaplan–Meier DFS curves for high versus low NFB subsets within the group B cases. As shown in Fig. 1 (panel B), the higher NFB p50 DNA-binding values were associated with significantly reduced DFS (P = 0.04). Likewise, the p65 DNA-binding DFS curves showed a similar trend, but their separation did not achieve statistical significance (P = 0.09).
|
B p50 and p65 DNA-binding values (Zhou et al. 2005). Mechanistically, the observed NFB correlation with ErbB2 expression could have resulted from the reported activation of the NFB pathway by ErbB2 RTK signaling (Romieu-Mourez et al. 2002, Biswas et al. 2004). Likewise, the NFB correlations with uPA expression and AP-1 DNA-binding probably reflect the fact that the uPA gene is known to be transcriptionally activated by both NFB and AP-1 transcription factor complexes working in concert (Hansen et al. 1992, Sliva et al. 2002). Given these mechanistic links and the fact that large clinical trials have consistently demonstrated that uPA expression independently identifies a high-risk subset of early-stage breast cancers (Eppenberger et al. 1998), it is tempting to conclude that tumor cell invasiveness and motility mediated by increased uPA expression and induced by activated NFB and AP-1 complexes contributed to the relapse rate and reduced DFS survival observed in our group B, ER-positive primary breast cancer cases that failed to benefit from adjuvant tamoxifen. |
NFB inhibition can reverse endocrine resistance
|
|---|
|
TopAbstractReceptor crosstalk and endocrine...NF{kappa}B in organ development...Importance of NF{kappa}B in...NF{kappa}B inhibition can...Targeting the NF{kappa}B pathway...References |
|---|
B p50 and p65 subunit DNA-binding activities were also assessed in a panel of breast cancer cell lines representing four different clinical phenotypes (ER-positive/ErbB2-negative, ER-positive/ErbB2-positive, ER-negative/ErbB2-positive, and ER-negative/ErbB2-negative). As shown in Fig. 2 (panel A), the ER-negative breast cancer cell lines SkBr3 and MDA231 exhibited significantly greater NFB p50 subunit DNA-binding than the ER-positive and tamoxifen-sensitive MCF7 and T47D breast cancer cell lines. Interestingly, the ER-positive/ErbB2-positive and tamoxifen-resistant BT474 and MCF7/HER2 cell lines exhibited intermediate NFB p50 DNA-binding activities. Among experimental and medicinal strategies to inhibit constitutively active NFB are drugs that target upstream NFB activating signals or downstream IB degradative mechanisms (Yamamoto & Gaynor 2001), including the potent and specific antioxidant pyrrolidine dithiocarbamate (Schreck et al. 1992), proteasome inhibitors such as MG-132 and PS-341 (bortezomib/Velcade) (Cordoso et al. 2004), and sesquiterpene lactones found in antiphlogistic plant extracts such as the specific IKK inhibitor, parthenolide (PA) (Hehner et al. 1999). To explore the endocrine-modulating role of NFB and attempt to restore tamoxifen sensitivity to our cell line models of high-risk, ER-positive breast cancers, we treated BT474 and MCF7/HER2 cell lines with tamoxifen, NFB-inhibiting doses of either PA or PS-341, or a combination of tamoxifen with PA or PS-341 (Zhou et al. 2005). For comparison, tamoxifen-sensitive MCF-7 cells were also subjected to these same treatments. Doses of PA and PS-341 that fully inhibit NFB activation in all three cell lines (Zhou et al. 2005) produced comparable growth inhibition of all these cells, as seen in Fig. 2 (panels B and C). While PA and PS-341 failed to enhance tamoxifen inhibition of MCF-7 growth, these same PA and PS-341 doses significantly enhanced tamoxifen growth inhibition of the resistant MCF7/HER2 and BT474 cells. These findings support the interpretation that ErbB2 RTK induction of NFB in MCF7/HER2 and BT474 cells renders them resistant to the antiestrogenic effects of tamoxifen, and this antiestrogenic effect is restored when the ErbB2-activated NFB pathway is inhibited by either the IKK inhibitor PA or the proteasome inhibitor PS-341. These findings are also consistent with a recent report demonstrating that inhibition of NFB by cotreatment with PA overcomes endocrine resistance induced in MCF7 cells by the constitutive overexpression of Akt (DeGraffenried et al. 2004). In vivo preclinical evaluation of the ability of PA and PS-341 to restore tamoxifen sensitivity is planned with nude mice implanted with MCF7/HER2 or BT474 breast tumor xenografts.
|
|
Targeting the NFB pathway in hormone-dependent breast cancer
|
|---|
|
TopAbstractReceptor crosstalk and endocrine...NF{kappa}B in organ development...Importance of NF{kappa}B in...NF{kappa}B inhibition can...Targeting the NF{kappa}B pathway...References |
|---|
B documented in various pathophysiologic disorders has been a major impetus for commercial development of new agents capable of inactivating the NFB pathway (Yamamoto & Gaynor 2001, Ghosh & Karin 2002, Feinman et al. 2004, Karin et al. 2004, Veiby & Read 2004). Much of this effort initially focused on blocking dysregulated NFB function in leukocytes to treat chronic inflammatory disorders and originated with the isolation of many different NFB-inhibiting, anti-inflammatory compounds from traditional medicines. However, with recent clinical approval of the protea-some inhibitor, bortezomib (PS-341), used at NFB-inhibiting doses to treat multiple myeloma, and with promising activity against assorted other malignancies (Cardoso et al. 2004), has come renewed enthusiasm for the preclinical development and evaluation of more specific, NFB pathway-inhibiting anticancer agents. A number of endogenous molecules have been identified as inhibitors of NFB, and these were recently proposed as new opportunities for the control of cancer (Chen 2004). Table 1 lists a number of structurally diverse, commercially available, natural and synthetic compounds with known NFB-inhibiting activity. Some of these have established anticancer activity (e.g. acrolein) or are functionally related to an approved anticancer agent (e.g. MG-132, lactacystin, epoxomicin); others have known cancer prevention properties (e.g. aspirin, sulindac), or are being investigated either for their ability to enhance cancer chemotherapy activity (e.g. parthenolide) or for their own intrinsic antineoplastic activity (e.g. betulinic acid, rocaglamide, trimethyl-D-sphingosine). However, most of these compounds are not so specifically targeted to the NFB pathway as are the IKK inhibitors (e.g. parthenolide, BAY11-7085), and this specificity may ultimately prove important if some measure of increased tumor NFB activity is used to select breast or other cancers for treatment with NFB inhibitors.
|
B pathway as one of the few proliferation and survival pathways commonly dysregulated in mouse and human mammary cancers (Hu et al. 2004), our recent study indicates that hormone-dependent, human breast cancers can be subset into those with and without dysregulated NFB, suggesting the need for a predictive biomarker, such as increased NFB p50 subunit DNA binding, to identify breast cancer patients most likely to benefit from a specific NFB inhibitor (Zhou et al. 2005). If In vivo studies confirm that NFB pathway inhibition improves the efficacy of endocrine treatment against ER-positive breast cancers with increased NFB p50 subunit DNA binding, then clinical trials can be designed to test this strategy even in the absence of specific NFB-inhibiting investigational drugs. The pathway schematic shown in Fig. 3 identifies known investigational agents potentially capable of interrupting intracellular signals immediately upstream and downstream of NFB activation, preventing its crosstalk and interference with the ER mechanism targeted by our standard endocrine agents.
|
|
Acknowledgements |
|---|
|
References |
|---|
|
TopAbstractReceptor crosstalk and endocrine...NF{kappa}B in organ development...Importance of NF{kappa}B in...NF{kappa}B inhibition can...Targeting the NF{kappa}B pathway...References |
|---|
Baeuerle PA & Baltimore D 1996 NF-B: ten years after. Cell 87 13–20.[CrossRef][Web of Science][Medline]
Baldwin AS 2001 Control of oncogenesis and cancer therapy resistance by the transcription factor NF-B. Journal of Clinical Investigation 107 241–246.[CrossRef][Web of Science][Medline]
Benz CC 2004a ErbB2/HER2 and other molecular pathways in ER-positive breast cancer: impact on endocrine resistance and clinical outcome. In: Endocrine Therapy in Breast Cancer. Eds M Dowsett & J Ingle. New York: Marcel Dekker.
Benz CC 2004b HER2 and endocrine response in breast cancer. Oncology Exchange 3 8–11, 21.
Benz CC, Scott GK, Sarup JC, Johnson RM, Tripathy D, Coronado E, Shepard HM & Osborne CK 1992 Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Research and Treatment 24 85–95.[CrossRef][Web of Science][Medline]
Bhat-Nakshatri P, Sweeney CJ & Nakshatri H 2002 Identification of signal transduction pathways involved in constitutive NF-kappaB activation in breast cancer cells. Oncogene 21 2066–2078.[CrossRef][Web of Science][Medline]
Biswas DK, Shi Q, Baily S, Strickland I, Ghosh S, Pardee ÅB & Iglehart JD 2004 NF-kappaB activation in human breast cancer specimens and its role in cell proliferation and apoptosis. PNAS 101 10137–10142.
Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S & Nakshatri H 2001 Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alphas: a new model for anti-estrogen resistance. Journal of Biological Chemistry 276 9817–9824.
Cao Y & Karin M 2003 NF-kappaB in mammary gland development and breast cancer. Journal of Mammary Gland Biology and Neoplasia 8 215–223.[CrossRef][Web of Science][Medline]
Cardoso F, Ross JS, Piccart MJ, Sotiriou C & Durbecq V 2004 Targeting the ubiquitin-proteasome pathway in breast cancer. Clinical Breast Cancer 5 148–157.[Medline]
Chen F 2004 Endogenous inhibitors of nuclear factor-B, an opportunity for cancer control. Cancer Research 64 8135–8138.
Chisamore MJ, Ahmed Y, Bentrem DJ, Jordan VC & Tonetti DA 2001 Novel antitumor effect of estradiol in athymic mice injected with a T47D breast cancer cell line overexpressing protein kinase Calpha. Clinical Cancer Research 7 3156–3165.
Chung YL, Sheu ML, Yang SC, Lin CH & Yen SH 2002 Resistance to tamoxifen-induced apoptosis is associated with direct interaction between Her2/neu and cell membrane estrogen receptor in breast cancer. International Journal of Cancer 97 306–312.[CrossRef][Web of Science][Medline]
Cogswell PC, Gutteridge DC, Funkhouser WK & Baldwin AS Jr 2000 Selective activation of NF-B subunits in human breast cancer: potential roles for /p52 and for Bcl-3. Oncogene 19 1123–1131.[CrossRef][Web of Science][Medline]
DeGraffenried LA, Chandrasekar B, Friedrichs WE, Donzis E, Silva J, Hidalgo M, Freeman JW & Weiss GR 2004 NF-B inhibition markedly enhances sensitivity of resistant breast tumor cells to tamoxifen. Annals of Oncology 15 885–890.
Dixit V & Mak TW 2002 NF-B signaling: many roads lead to Madrid. Cell 111 615–619.[CrossRef][Web of Science][Medline]
Dowsett M 2001 Overexpression of HER-2 as a resistance mechanism to hormonal therapy for breast cancer. Endocrine-Related Cancer 8 191–195.[Abstract]
Elledge RM & Fuqua SAW 2000 Estrogen and progesterone receptors. In Diseases of the Breast, 2nd edn, pp 471–488. Eds JR Harris, ME Lippman, M Morrow & CK Osborne. Philadelphia: Lippincott Williams & Wilkins.
Eppenberger U, Kueng W, Schlaeppi J-M, Roesel JL, Benz C, Mueller H, Matter A, Zuber M, Leuscher K, Litschg, M, Schmitt M, Foekens JA & Eppenberger-Castori S 1998 Makers of tumor angiogenesis and proteolysis independently define high- and low-risk subsets of node-negative breast cancer patients. Journal of Clinical Oncology 16 3129–3136.
Eppenberger-Castori S, Kueng W, Benz CC, Paris K, Caduff R, Bannwart F, Fink D, Dieterich H, Braschler C, von Castelberg B, Muller H & Eppenberger U 2001 Prognostic and predictive significance of ErbB2 breast tumor levels measured by enzyme-immunoassay (EIA). Journal of Clinical Oncology 19 645–656.
Ghosh S & Karin M 2002 Missing pieces in the NF-B puzzle. Cell 109 81s–96s.
Ghosh S, May MJ & Kopp EB 1998 NF-kappaB and Rel proteins: evolutionarily conserved mediators of immune response. Annual Review of Immunology 16 225–260.[CrossRef][Web of Science][Medline]
Giardina C & Hubbard AK 2002 Growing old with nuclear factor-kappaB. Cell Stress Chaperones 7 207–212.[CrossRef][Web of Science][Medline]
Gruvberger S, Ringner M, Chen Y, Panavally S, Saal LH, Borg A, Ferno M, Peterson C & Meltzer PS 2001 Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns. Cancer Research 61 5979–5984.
Hansen SK, Nerlov C, Zabel U, Verde P, Johnsen M, Baeuerle PA & Blasi F 1992 A novel complex between the p65 subunit of NF-B and c-Rel binds to a DNA element involved in the phorbol ester induction of the human urokinase gene. EMBO Journal 11 205–213.[Medline]
Harnish DC, Scicchitano MS, Adelman SJ, Lyttle CR & Karathanasis SK 2000 The role of CBP in estrogen receptor cross-talk with nuclear factor-kappaB in HepG2 cells. Endocrinology 141 3403–3411.
Hehner SP, Hofmann TG, Droge W & Schmitz ML 1999 The anti-inflammatory sesquiterpene lactone parthenolide inhibits NF-B by targeting the IB kinase complex. Journal of Immunology 163 5617–5623.
Hu Y, Sun H, Drake J, Kittrell F, Abba MC, Deng L, Gaddis S, Sahin A, Baggerly K, Medina D & Åldaz CM 2004 From mice to humans: identification of commonly deregulated genes in mammary cancer via comparative SAGE studies. Cancer Research 64 7748–7755.
Johnston SR, Lu B, Scott GK, Kushner PJ, Smith IE, Dowsett M & Benz CC 1999 Increased activator protein-1 DNA binding and c-Jun NH2-terminal kinase activity in human breast tumors with acquired tamoxifen resistance. Clinical Cancer Research 5 251–256.
Karin M & Lin A 2002 NF-B at the crossroads of life and death. Nature Immunology 3 221–227.[CrossRef][Web of Science][Medline]
Karin M, Yamamoto Y & Wang QM 2004 The IKK NF-kappaB system: a treasure trove for drug development. Nature Reviews. Drug Discovery 3 17–26.[CrossRef][Web of Science][Medline]
Keana MM, Rubinstein Y, Cuello M, Ettenberg SA, Banerjee P & Nau MM 2000 Inhibition of NF-kappaB activity enhances TRAIL mediated apoptosis in breast cancer cell lines. Breast Cancer Research and Treatment 64 211–219.[CrossRef][Web of Science][Medline]
Konecny G, Pauletti G, Pegram M, Untch M, Dandekar S, Aguilar Z, Wilson C, Rong H-M, Bauerfeind I, Felber M, Wang H-J, Beryt M, Seshadri R, Hepp H & Slamon DJ 2003 Quantitative association between HER2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. Journal of the National Cancer Institute 95 142–153.
Kurokawa H & Arteaga CL 2003 ErbB (HER) receptors can abrogate antiestrogen action in human breast cancer by multiple signaling mechanisms. Clinical Cancer Research 9 511s–515s.
Kurokawa H, Lenferink AEG, Simpson JF, Pisacane PI, Sliwkowski MX, Forbes JT & Arteaga CL 2000 Inhibition of HER2/neu (erbB2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells. Cancer Research 60 5887–5894.
McGuire WL 1980 Steroid hormone receptors in breast cancer treatment strategy. Recent Progress in Hormone Research 36 135–156.[Medline]
Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet RJ Jr & Sledge GW Jr 1997 Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Molecular and Cellular Biology 17 3629–3639.
Pahl HL 1999 Activators and target genes of Rel/NF-B transcription factors. Oncogene 18 6853–6866.[CrossRef][Web of Science][Medline]
Parisot JP, Hu XF, DeLuise M & Zalcberg JR 1999 Altered expression of the IGF-1 receptor in a tamoxifen-resistant human breast cancer cell line. British Journal of Cancer 79 693–700.[CrossRef][Web of Science][Medline]
Pratt MA, Bishop TE, White D, Yasvinski G, Menard M, Niu MY & Clarke R 2003 Estrogen withdrawal-induced NF-kappaB activity and bcl-3 expression in breast cancer cells: roles in growth and hormone independence. Molecular and Cellular Biology 23 6887–6900.
Quong J, Eppenberger-Castori S, Moore D, Scott GK, Birrer MJ, Kueng W, Eppenberger U & Benz CC 2002 Age-dependent changes in breast cancer hormone receptors and oxidant stress markers. Breast Cancer Research and Treatment 76 221–236.[CrossRef][Web of Science][Medline]
Romieu-Mourez R, Landesman-Bollag E, Seldin DC & Sonnenshein GE 2002 Protein kinase CK2 promotes aberrant activation of nuclear factor-kappaB, transformed phenotype, and survival of breast cancer cells. Cancer Research 62 6770–6778.
Schiff R, Reddy P, Ahotupa M, Coronado-Heinsohn E, Grim M, Hilsenbeck SG, Lawrence R, Deneke S, Herrera R, Chamness GC, Fuqua SA, Brown PH & Osborne CK 2000 Oxidative stress and AP-1 activity in tamoxifen-resistant breast tumors in vivo. Journal of the National Cancer Institute 92 1926–1934.
Schiff R, Massarweh SA, Shou J, Bharwani L, Mohsin Í K & Osborne CK 2004 Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance. Clinical Cancer Research 10 331s–336s.
Schreck R, Meier B, Mannel DN, Droge W & Baeuerle PA 1992 Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. Journal of Experimental Medicine 175 1181–1194.
Shou J, Massarweh S, Osborne CK, Wakeling AE, Åli S, Weiss H & Schiff R 2004 Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. Journal of the National Cancer Institute 96 926–935.
Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S & Boyd MR 1990 New colorimetric cytotoxicity assay for anticancer-drug screening. Journal of the National Cancer Institute 82 1107–1112.
Sliva D, English D, Lyons D & Lloyd FP Jr 2002 Protein kinase C induces motility of breast cancers by upregulating secretion of urokinase-type plasminogen activator through activation of AP-1 and NF-B. Biochemical and Biophysical Research Communications 290 552–557.[CrossRef][Web of Science][Medline]
Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnson H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lonning PE & Borresen-Dale A-L 2001 Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. PNAS 98 10869–10874.
Sovak MA, Bellas RE, Kim DW, Zanieski GJ, Rogers AE, Traish AM & Sonenshein GE 1997 Aberrant nuclear factor-B/Rel expression and the pathogenesis of breast cancer. Journal of Clinical Investigation 100 2952–2960.[Web of Science][Medline]
Speir E, Yu ZX, Takeda K, Ferrans VJ & Cannon RO 2000 Competition for p300 regulates transcription by estrogen receptor and nuclear factor-kappaB in human coronary smooth muscle cells. Circulation Research 87 1006–1011.
Sun WH, Keller ET, Stebler BS & Ershler WB 1998 Estrogen inhibits phorbol ester-induced I kappa B alpha transcription and protein degradation. Biochemical and Biophysical Research Communications 244 691–695.[CrossRef][Web of Science][Medline]
Veiby OP & Read MA 2004 Chemoresistance: impact of nuclear factor (NF)-B inhibition by small interfering RNA. Clinical Cancer Research 10 3262–3264.
Vertegaal AC, Kuiperij HB, Yamaoka S, Courtois G, van der Eb AJ & Zantema A 2000 Protein kinase C-alpha is an upstream activator of the IkappaB kinase complex in the TPA signal transduction pathway to NF-kappaB in U2OS cells. Cellular Signalling 12 759–768.[CrossRef][Web of Science][Medline]
Wang CY, Cusack JC Jr, Liu R & Baldwin AS Jr 1999 Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappaB. Nature Medicine 5 412–417.[CrossRef][Web of Science][Medline]
Yamamoto Y & Gaynor RB 2001 Therapeutic potential of inhibiton of the NF-B pathway in the treatment of inflammation and cancer. Journal of Clinical Investigation 107 135–142.[Web of Science][Medline]
Zhou BP, Hu MC, Miller SA, Yu Z, Xia W, Lin SY & Hung MC 2000 HER-2/neu blocks tumor necrosis factor-induced apoptosis via the Akt/NF-kappaB pathway. Journal of Biological Chemistry 275 8027–8031.
Zhou YM, Eppenberger-Castori S, Marx C, Yau C, Scott GK, Eppenberger U & Benz CC 2005 Activation of nuclear factor-B (NF-B) identifies a high-risk subset of hormone-dependent breast cancers. International Journal of Biochemistry and Cell Biology 37 1130–1144.[CrossRef][Web of Science][Medline]
This article has been cited by other articles:
|
|
 |
|
  J. Frasor, A. Weaver, M. Pradhan, Y. Dai, L. D. Miller, C.-Y. Lin, and A. Stanculescu Positive Cross-Talk between Estrogen Receptor and NF-{kappa}B in Breast Cancer Cancer Res., December 1, 2009; 69(23): 8918 - 8925. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ahmed, E. Valen, A. Sandelin, and J. Matthews Dioxin Increases the Interaction Between Aryl Hydrocarbon Receptor and Estrogen Receptor Alpha at Human Promoters Toxicol. Sci., October 1, 2009; 111(2): 254 - 266. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-R. Weng, C.-H. Tsai, H. A. Omar, A. M. Sargeant, D. Wang, S. K. Kulp, C. L. Shapiro, and C.-S. Chen OSU-A9, a potent indole-3-carbinol derivative, suppresses breast tumor growth by targeting the Akt-NF-{kappa}B pathway and stress response signaling Carcinogenesis, October 1, 2009; 30(10): 1702 - 1709. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Copetti, C. Bertoli, E. Dalla, F. Demarchi, and C. Schneider p65/RelA Modulates BECN1 Transcription and Autophagy Mol. Cell. Biol., May 15, 2009; 29(10): 2594 - 2608. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Chanrion, V. Negre, H. Fontaine, N. Salvetat, F. Bibeau, G. M. Grogan, L. Mauriac, D. Katsaros, F. Molina, C. Theillet, et al. A Gene Expression Signature that Can Predict the Recurrence of Tamoxifen-Treated Primary Breast Cancer Clin. Cancer Res., March 15, 2008; 14(6): 1744 - 1752. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J M W Gee, V E Shaw, S E Hiscox, R A McClelland, N K Rushmere, and R I Nicholson Deciphering antihormone-induced compensatory mechanisms in breast cancer and their therapeutic implications Endocr. Relat. Cancer, December 1, 2006; 13(Supplement_1): S77 - S88. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Lin, Y. Yu, H. Zhao, Y. Zhang, J. Manela, and D. A. Tonetti Overexpression of PKC{alpha} is required to impart estradiol inhibition and tamoxifen-resistance in a T47D human breast cancer tumor model Carcinogenesis, August 1, 2006; 27(8): 1538 - 1546. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-S. Nam, M.-J. Kang, A. M. Suchar, T. Shimamura, E. A. Kohn, A. M. Michalowska, V. C. Jordan, S. Hirohashi, and L. M. Wakefield Chemokine (C-C motif) ligand 2 mediates the prometastatic effect of dysadherin in human breast cancer cells. Cancer Res., July 15, 2006; 66(14): 7176 - 7184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Rayala, J. Mascarenhas, R. K. Vadlamudi, and R. Kumar Altered localization of a coactivator sensitizes breast cancer cells to tumor necrosis factor-induced apoptosis. Mol. Cancer Ther., February 1, 2006; 5(2): 230 - 237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J M W Gee, A Howell, W J Gullick, C C Benz, R L Sutherland, R J Santen, L-A Martin, F Ciardiello, W R Miller, M Dowsett, et al. Consensus Statement Endocr. Relat. Cancer, July 1, 2005; 12(Supplement_1): S1 - S7. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
