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. 2013 Jan;5(1):17–24. doi: 10.1177/1758834012457437

Combining Notch inhibition with current therapies for breast cancer treatment

Keith Brennan 1,✉, Robert B Clarke 2
PMCID: PMC3539271  PMID: 23323144

Abstract

Over recent years, there has been an increasing interest in targeting Notch signalling for the treatment of breast cancer. This has stemmed from the realization that many Notch pathway components display altered expression in breast cancer, and that Notch signalling impacts on many of the cellular properties associated with tumour initiation and progression. Consequently, Notch pathway inhibitors are now entering the initial stages of clinical trials. However, there is a definite need to consider how best to use these inhibitors and therefore which treatment strategies are likely to yield the most promising results. In particular, recent studies suggest that the greatest success will come from combining Notch pathway inhibitors with current breast cancer therapies.

Keywords: Notch, breast cancer, Notch inhibitors, combination therapy

Aberrant activation of Notch signalling in breast cancer

Several groups have now reported altered expression of Notch pathway components in breast cancer [Farnie et al. 2007; Lee et al. 2008b; Li et al. 2010; Mittal et al. 2009; Pece et al. 2004; Reedijk et al. 2005; Reedijk et al. 2008; Rizzo et al. 2008; Stylianou et al. 2006; Yao et al. 2011; Zardawi et al. 2010]. These studies have primarily focused on the Notch receptors themselves and the ligands that activate the pathway, Jagged1&2 and Delta-like1,3&4, in invasive carcinoma. For example, elevated expression of Notch1 and Jagged1 has been reported and shown to associate with poor prognosis and basal breast cancer [Reedijk et al. 2005, 2008]. Similarly, downregulation of Numb, a negative regulator of the pathway, has been associated with high-grade breast cancers [Pece et al. 2004]. There is, however, no clear indication that upregulation of Notch pathway components associates with a particular breast cancer subtype, with different groups demonstrating an upregulation of Notch1 in oestrogen receptor positive (ER+ve) [Rizzo et al. 2008], human epidermal growth factor receptor 2 positive (Her2+ve) [Zardawi et al. 2010] and triple-negative/basal breast cancer [Lee et al. 2008b; Reedijk et al. 2008].

There are also several studies showing that Notch pathway components are upregulated in early noninvasive stages of breast cancer, including usual ductal hyperplasia (UDH) and ductal carcinoma in situ (DCIS) [Farnie et al. 2007; Mittal et al. 2009; Zardawi et al. 2010]. These studies indicate that changes in the Notch pathway occur early in breast cancer progression and therefore changes in Notch signalling may play an important role in the initiation of the disease. Interestingly, one study also demonstrates that in DCIS, activation of the Notch pathway correlates with disease recurrence within 5 years, suggesting that pathway activation may associate with more aggressive and treatment resistant forms [Farnie et al. 2007].

Although all of this work strongly suggests that Notch signalling is activated in breast cancer, there are many ways by which signalling through the pathway is regulated [Bray, 2006]. For example, modification of Notch by the Fringe glycosyltransferases can both increase and decrease the ability of a Jagged or Delta-like ligand to activate Notch [Rana and Haltiwanger, 2011; Yang et al. 2005]. Therefore, overexpression of Notch ligands and receptors do not necessarily indicate that the pathway is activated. However, several studies have looked at the γ-secretase mediated cleavage of the Notch1 protein or the expression of Hes/Hey genes, both of which are indicative of Notch signalling [Farnie et al. 2007; Mittal et al. 2009; Stylianou et al. 2006]. Also several genetic rearrangements have been identified very recently in breast cancer samples and cell lines within the Notch1 and Notch2 genes that lead to the production of an active form the receptors [Robinson et al. 2011]. From these studies it is clear that Notch signalling is aberrantly activated in a broad range of breast cancer subtypes compared with normal breast tissue. However, it is interesting to note that all but one of the genetic rearrangements within the Notch1 and Notch2 genes were found within triple-negative breast cancer samples, suggesting that sustained Notch signalling is more important within this subtype [Robinson et al. 2011].

Notch signalling alters many cellular properties in breast cancer

Notch signalling has long been known to play a major role in cell fate specification during embryonic development [Andersson et al. 2011; Bolos et al. 2007]. However, it has become increasingly clear that Notch signalling affects many other cellular properties, including proliferation [Lee et al. 2008a; Rizzo et al. 2008], apoptosis [Meurette et al. 2009; Stylianou et al. 2006], epithelial–mesenchymal transition (EMT) [Leong et al. 2007], stem cell self-renewal [Farnie et al. 2007; Harrison et al. 2010] and angiogenesis [Zeng et al. 2005]. This is not really surprising, and simply reflects the multifaceted roles for Notch in development. The effect of Notch signalling, however, can vary between tissues or within an individual tissue between disease states. For example, Notch signalling has been shown to promote stem cell self-renewal in intestinal stem cells [Pellegrinet et al. 2011], whilst it promotes the differentiation of mammary gland [Bouras et al. 2008] and epidermal stem cells [Lowell et al. 2000]. Similarly, Notch signalling induces p21 expression and slows the cell cycle in normal keratinocytes and mammary epithelial cells ([Rangarajan et al. 2001] and Stylianou and Brennan, unpublished observation), but promotes proliferation in breast cancer cell lines by upregulating cyclin A and B expression [Rizzo et al. 2008]. This apparent inconsistency is almost certainly due to Notch signals being interpreted differently in different tissues resulting in the expression of distinct groups of target genes [Bernard et al. 2010]. This said, there are cases where Notch signalling consistently affects a particular cellular property. For example, Notch signalling promotes an EMT in mammary gland, kidney, endocardial and epidermal cells by inducing the expression of members of the Snail family of transcription factors [Leong et al. 2007; Timmerman et al. 2004; Zavadil et al. 2004]. This difference in the regulation of cellular properties may reflect how directly Notch signalling controls these processes [Schwanbeck et al. 2011]. In the case of EMT, Notch signals directly regulate the expression of Snail and Slug and binding sites for CSL proteins have been identified in the promoters of both genes [Leong et al. 2007; Sahlgren et al. 2008]. On the other hand, the effects on cell cycle are likely to be indirect and therefore more influenced by the other signals and transcription factors present within the cell leading to different responses in different cell types.

Within breast cancer, Notch signalling has been shown to affect all of these cellular properties. It induces expression of cyclin A and cyclin B to promote cell division [Rizzo et al. 2008]. It activates Akt signalling to provide protection against a wide range of apoptotic stimuli, including commonly used chemotherapeutic agents [Meurette et al. 2009; Stylianou et al. 2006]. It induces the expression of Slug and therefore promotes an EMT in breast cancer cells [Leong et al. 2007]. It induces angiogenesis in the surrounding stroma [O’Neill et al. 2007]. It also promotes the self-renewal of breast cancer stem cells [Farnie et al. 2007; Harrison et al. 2010]. However, there does appear to be some receptor specificity as Notch4 is much more important than Notch1 for the renewal of breast cancer stem cells [Farnie et al. 2007; Harrison et al. 2010], whilst increased Notch2 signalling appears to prevent tumour formation [O’Neill et al. 2007]. Similarly, Notch3, but not Notch1, appears to be essential for the anti-apoptotic effect of Notch signalling in Her2-ve breast cancers [Yamaguchi et al. 2008]. This said, elevated Notch signalling clearly plays many roles in breast cancer making it a very attractive pathway to target [Arcaroli et al. 2011; Pannuti et al. 2010]. Importantly, it plays a role in both bulk tumour cells and cancer stem cells, ensuring that targeting the Notch pathway will not only reduce tumour bulk but should also reduce the likelihood of recurrence. It is also worth noting that Notch pathway inhibitors have affects with the surrounding tumour stroma that curtail tumour growth by inducing haemorrhage and hypoxia through their effects on endothelial cells [Cook et al. 2012; Dufraine et al. 2008; Rizzo et al. 2008].

Many ways to inhibit the Notch pathway

Notch signalling is activated by the interaction of Jagged1&2 and Delta-like1,3&4 transmembrane ligands with Notch receptors (1–4) on adjacent cells [Bray, 2006]. This leads to the endocytosis of ligands into the signal-sending cell, placing a physical strain on the bound Notch protein within the signal-receiving cell [Musse et al. 2012]. This causes a conformational change within the extracellular domain of the Notch proteins that exposes a cleavage site for the ADAM proteins Kuzbanian (ADAM10) and TACE (ADAM17) [van Tetering et al. 2009]. Cleavage at this site leads to endocytosis of the Notch extracellular domain into the signal-sending cell [Parks et al. 2000] and the generation of a signalling intermediate known as NEXT (Notch extracellular truncation) in the signal-receiving cell [Mumm et al. 2000]. NEXT is a substrate for γ-secretase, a protease that comprises Presenilin1 or 2, Nicastrin, APH-1 and Pen-2. γ-secretase cleaves NEXT twice within the transmembrane domain to release the Notch intracellular domain (NICD) that translocates to the nucleus [Okochi et al. 2002]. Within the nucleus, NICD interacts with members of the CSL family of DNA-binding proteins, displacing transcriptional corepressors associated with the CSL proteins and recruiting members of the Mastermind-like (MAML) family of transcriptional co-activators [Arnett et al. 2010]. The genes transcribed differ greatly between tissues, and are influenced by the number of receptors activated [Bernard et al. 2010; Mazzone et al. 2010; Schwanbeck et al. 2011]. However, members of the Hes/Hey family of transcriptional corepressors are frequently induced and can be seen as common targets [Fischer and Gessler, 2007].

Over recent years many approaches have been taken to inhibit the Notch pathway. The first Notch pathway inhibitors, used both experimentally and clinically, were the γ-secretase inhibitors which prevent cleavage of NEXT and therefore the release of NICD from the plasma membrane [Arcaroli et al. 2011; Pannuti et al. 2010; van Es et al. 2005]. More recently, monoclonal antibodies that recognise specific ligands (Dll4) [Hoey et al. 2009] or receptors (Notch1-3) [Aste-Amezaga et al. 2010; Aveo Pharmaceuticals; Li et al. 2008; Wu et al. 2010] have been developed. These either prevent ligand/receptor interaction or the conformational change within the extracellular domain required to expose the Kuzbanian or TACE cleavage site. Agents that target the RBPjk/NICD/MAML transcriptional activator complex have also been generated. These agents, SAHM1 [Moellering et al. 2009] and TR4 [Epenetos et al. 2009], compete with MAML for binding to RBPjk/NICD. Consequently, if SAHM1 or TR4 are present in excess, the RBPjk/NICD/MAML complex will fail to form. As the transcription of Notch pathway target genes is dependent upon the transcription activation domain present within the MAML proteins, treatment with SAHM1 or TR4 will inhibit Notch signalling.

The γ-secretase inhibitors, SAHM1 and TR4 have the benefit that they can disrupt signalling by all four Notch receptors. However, there are also some advantages to targeting individual Notch pathway receptors and ligands, as pan-inhibition of Notch signalling with γ-secretase inhibitors has been associated with goblet cell dysplasia in the gut [Arcaroli et al. 2011; Pannuti et al. 2010; van Es et al. 2005; Wu et al. 2010]. This said, changes in the treatment regime for γ-secretase inhibitors have helped to reduce these problems. Also, both SAHM1 and TR4 seem to be well tolerated [Epenetos et al. 2009; Moellering et al. 2009]. It is also worth noting that long-term treatment with Notch pathway inhibitors is associated with development of vascular tumours [Liu et al. 2011; Yan et al. 2010].

Notch pathway inhibitors are unlikely to be useful as a monotherapy

Initial work with γ-secretase inhibitors suggested that their use alone may be sufficient to reduce the growth of xenograft tumours derived from breast cancer cell lines by inhibiting proliferation and inducing apoptosis [Lee et al. 2008a; Rizzo et al. 2008]. Subsequent work, however, suggests that cytotoxic effects seen in the xenograft tumours are due to off-target effects of the γ-secretase inhibitors used on proteasome function [Han et al. 2009]. In an elegant series of experiments, the Allalunis–Turner laboratory has shown that the γ-secretase inhibitor Z-Leu-Leu-Nle-CHO (GSI I) can inhibit proteosomal function unlike the γ-secretase inhibitors DAPT (GSI IX) and L685,458 (GSI X) [Han et al. 2009]. They also found that only Z-Leu-Leu-Nle-CHO treatment can induce apoptosis in breast cancer cell lines and that this effect can be rescued by restoring proteosomal function with the antioxidant edaravone. In keeping with this, others have shown that inhibiting Notch signalling genetically by overexpressing the pathway inhibitor Numb or a dominant negative form of MAML fails to induce apoptosis in the absence of additional pro-apoptotic signals [Meurette et al. 2009; Stylianou et al. 2006].

Notch pathways inhibitors increase the effectiveness of current therapies

Despite the apparent ineffectiveness of Notch pathway inhibitors on their own, several lines of evidence indicate that they will be very useful in combination with the current therapies used for ER+ve, Her2+ve and triple-negative breast cancers. In fact, they may prove to be particularly useful for resensitizing therapy-resistant ER+ve [Haughian et al. 2011; Rizzo et al. 2008] and Her2+ve [Kondratyev et al. 2012; Osipo et al. 2008; Pandya et al. 2011] breast cancers to anti-oestrogen and anti-Her2 therapies, respectively.

In cell-line models of anti-oestrogen therapy resistance, Notch signalling is elevated compared with the parental therapy-sensitive cell lines [Haughian et al. 2011; Rizzo et al. 2008]. Furthermore, work with these models demonstrated that combining Notch pathway inhibitors with anti-oestrogen therapies enhances the response of therapy-sensitive cell lines, and resensitizes therapy-resistant cell lines to the anti-oestrogen therapy. Interestingly, a very recent paper indicates that the increase in Notch signalling observed in therapy-resistant ER+ve cell lines does not occur in all cells but rather within an ER-ve/cytokeratin 5 positive (CK5+ve) subpopulation of cells [Haughian et al. 2011]. Expression profiling indicates that these ER-ve/CK5+ve cells are similar to basal or triple-negative breast cancer cell lines and tissue samples. Given the recent suggestion that basal breast cancers are derived from progenitor cells [Lim et al. 2009; Prat and Perou, 2009], it is possible that these ER-ve/CK5+ve cells represent a stem or progenitor cell-like population within the cell lines [Liu and Wicha, 2010]. Interestingly, the presence of ER-ve/CK5+ve cells also correlates with the development of resistance to anti-oestrogen therapies, and their number is regulated by Notch signalling [Haughian et al. 2011]. Consequently, inhibiting Notch signalling reduces the number of ER-ve/CK5+ve cells and resensitizes therapy-resistant ER+ve cell lines to anti-oestrogen therapies.

Similarly in cell line models of anti-Her2 therapy resistance, Notch signalling is seen to increase in therapy-resistant cell lines [Kondratyev et al. 2012; Osipo et al. 2008; Pandya et al. 2011]. Again, inhibiting Notch signalling resensitizes therapy-resistant cell lines to anti-Her2 therapy. Importantly, this has also been shown with in vivo xenograft tumours, indicating that this approach is likely to be successful therapeutically [Pandya et al. 2011]. Interestingly, a recent paper shows that combined GSI/anti-Her2 therapy can prevent recurrence of Her2 overexpressing xenografts [Pandya et al. 2011]. In these experiments, therapy-sensitive Her2 overexpressing xenograft tumours were established. These were then shrunk through treatment with anti-Her2 therapy or a combination of GSI and anti-Her2 therapy. When treatment was ceased, recurrence was seen following anti-Her2 therapy but not the combination therapy. Similarly, treatment of a mouse model of Her2+ve breast cancer with a GSI shrank the tumours and no recurrence was observed [Kondratyev et al. 2012]. As recurrence is thought to be driven by breast cancer stem cells [Liu and Wicha, 2010], this result, like those with the oestrogen-resistant cell lines, suggests that Notch pathway inhibitors target stem or progenitor-like cells within a tumour.

Furthermore, Notch pathway inhibitors have been shown to potentiate the effect of DNA-damaging chemotherapeutic agents, including doxorubicin, in a wide range of different breast cancer cell lines [Cho et al. 2011; Hoey et al. 2009; Meurette et al. 2009; Stylianou et al. 2006; Zang et al. 2010]. This suggests that Notch pathway inhibitors will prove useful for the treatment of triple-negative breast cancers which are treated primarily through surgery and chemotherapy. Interestingly many triple negative breast cancers initially respond well to chemotherapy but soon develop resistance [Carey et al. 2010]. It would be interesting to determine whether this resistance is due to activation of Notch signalling, and whether combined chemotherapy and Notch pathway inhibitors will improve treatment of this breast cancer subtype. Notch pathway inhibitors may also prove useful for the treatment of triple negative breast cancers because many of these tumours display enhanced EGFR signalling, and synergy has been seen when between anti-EGFR treatment and Compound E (GSI XXI) in this context [Dong et al. 2010].

Conclusion

Work over the last decade has shown that Notch signalling is aberrantly activated in breast cancer and that it regulates many of the cellular properties associated with transformation. This has led to significant interest in the use of Notch pathway inhibitors for breast cancer treatment, especially as they are expected to have effects in bulk tumour cells, cancer stem cells and the surrounding tumour stroma. The question now is how best to use these inhibitors in clinical trials. Current preclinical work indicates that Notch pathway inhibitors are unlikely to be effective on their own, but that they should significantly increase the efficacy of current therapies. This said, there is still a need to identify patients that are likely to respond to Notch pathway inhibitors [He et al. 2011; Watters et al. 2009]. Finally, the preclinical studies have raised one possible note of caution to the pan-inhibition of Notch signalling for breast cancer treatment, as a couple of studies have indicated that Notch2 signalling may have a tumour-suppressive role in breast cancer [O’Neill et al. 2007; Parr et al. 2004].

Footnotes

Funding: We would like to thank the Breast Cancer Campaign for their generous funding of our laboratories.

Conflict of interest statement: The authors declare no conflicts of interest in preparing this article.

Contributor Information

Keith Brennan, Wellcome Trust Centre for Cell-Matrix Research and Manchester Breast Centre, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.

Robert B. Clarke, Breast Biology and Manchester Breast Centre, School of Cancer, Enabling Sciences and Technology, University of Manchester, Manchester Academic Health Science Centre, Paterson Institute for Cancer Research, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK

References

  1. Andersson E., Sandberg R., Lendahl U. (2011) Notch signaling: simplicity in design, versatility in function. Development 138: 3593–3612 [DOI] [PubMed] [Google Scholar]
  2. Arcaroli J., Dasari A., Messersmith W., Jimeno A. (2011) γ-Secretase inhibitors in solid tumor malignancies. Drugs Fut 36: 677–690 [Google Scholar]
  3. Arnett K., Hass M., McArthur D., Ilagan M., Aster J., Kopan R., et al. (2010) Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes. Nat Struct Mol Biol 17: 1312–1317 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Aste-Amezaga M., Zhang N., Lineberger J., Arnold B., Toner T., Gu M., et al. (2010) Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors. PLoS One 5(2): e9094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Aveo Pharmaceuticals, I. Notch Program Available at: http://www.aveopharma.com/discovery_programs/notch_program/
  6. Bernard F., Krejci A., Housden B., Adryan B., Bray S. (2010) Specificity of Notch pathway activation: twist controls the transcriptional output in adult muscle progenitors. Development 137: 2633–2642 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bolos V., Grego-Bessa J., de la Pompa J. (2007) Notch signaling in development and cancer. Endocr Rev 28: 339–363 [DOI] [PubMed] [Google Scholar]
  8. Bouras T., Pal B., Vaillant F., Harburg G., Asselin-Labat M., Oakes S., et al. (2008) Notch signaling regulates mammary stem cell function and luminal cell-fate commitment. Cell Stem Cell 3: 429–441 [DOI] [PubMed] [Google Scholar]
  9. Bray S. (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7: 678–689 [DOI] [PubMed] [Google Scholar]
  10. Carey L., Winer E., Viale G., Cameron D., Gianni L. (2010) Triple-negative breast cancer: disease entity or title of convenience? Nat Rev Clin Oncol 7: 683–692 [DOI] [PubMed] [Google Scholar]
  11. Cho S., Lu M., He X., Ee P., Bhat U., Schneider E., et al. (2011) Notch1 regulates the expression of the multidrug resistance gene ABCC1/MRP1 in cultured cancer cells. Proc Natl Acad Sci U S A 108: 20778–20783 [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cook N., Frese K., Bapiro T., Jacobetz M., Gopinathan A., Miller J., et al. (2012) Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma. J Exp Med 209: 437–444 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dong Y., Li A., Wang J., Weber J., Michel L. (2010) Synthetic lethality through combined Notch-epidermal growth factor receptor pathway inhibition in basal-like breast cancer. Cancer Res 70: 5465–5474 [DOI] [PubMed] [Google Scholar]
  14. Dufraine J., Funahashi Y., Kitajewski J. (2008) Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene 27: 5132–5137 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Epenetos A., Kosparou C., Stylianou S. (2009) Inhibition of Notch signaling for the treatment of human carcinomas. In: Proceedings of the American Assocication of Cancer Research, 18–22 April, Denver, CO [Google Scholar]
  16. Farnie G., Clarke R., Spence K., Pinnock N., Brennan K., Anderson N., et al. (2007) Novel cell culture technique for primary ductal carcinoma in situ: role of Notch and epidermal growth factor receptor signaling pathways. J Natl Cancer Inst 99: 616–627 [DOI] [PubMed] [Google Scholar]
  17. Fischer A., Gessler M. (2007) Delta-Notch–and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors. Nucleic Acids Res 35: 4583–4596 [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Han J., Ma I., Hendzel M., Allalunis-Turner J. (2009) The cytotoxicity of gamma-secretase inhibitor I to breast cancer cells is mediated by proteasome inhibition, not by gamma-secretase inhibition. Breast Cancer Res 11(4): R57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Harrison H., Farnie G., Howell S., Rock R., Stylianou S., Brennan K., et al. (2010) Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res 70: 709–718 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Haughian J., Pinto M., Harrell J., Bliesner B., Joensuu K., Dye W., et al. (2011) Maintenance of hormone responsiveness in luminal breast cancers by suppression of Notch. Proc Natl Acad Sci U S A 109: 2742–2747 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. He W., Luistro L., Carvajal D., Smith M., Nevins T., Yin X., et al. (2011) High tumor levels of IL6 and IL8 abrogate preclinical efficacy of the gamma-secretase inhibitor, RO4929097. Mol Oncol 5: 292–301 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hoey T., Yen W., Axelrod F., Basi J., Donigian L., Dylla S., et al. (2009) DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell 5: 168–177 [DOI] [PubMed] [Google Scholar]
  23. Kondratyev M., Kreso A., Hallett R., Girgis-Gabardo A., Barcelon M., Ilieva D., et al. (2012) Gamma-secretase inhibitors target tumor-initiating cells in a mouse model of ERBB2 breast cancer. Oncogene 31: 93–103 [DOI] [PubMed] [Google Scholar]
  24. Lee C., Raskett C., Prudovsky I., Altieri D. (2008a) Molecular dependence of estrogen receptor-negative breast cancer on a notch-survivin signaling axis. Cancer Res 68: 5273–5281 [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lee C., Simin K., Liu Q., Plescia J., Guha M., Khan A., et al. (2008b) A functional Notch-survivin gene signature in basal breast cancer. Breast Cancer Res 10(6): R97. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Leong K., Niessen K., Kulic I., Raouf A., Eaves C., Pollet I., et al. (2007) Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J Exp Med 204: 2935–2948 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Li K., Li Y., Wu W., Gordon W., Chang D., Lu M., et al. (2008) Modulation of Notch signaling by antibodies specific for the extracellular negative regulatory region of NOTCH3. J Biol Chem 283: 8046–8054 [DOI] [PubMed] [Google Scholar]
  28. Li Y., Burns J., Cheney C., Zhang N., Vitelli S., Wang F., et al. (2010) Distinct expression profiles of Notch-1 protein in human solid tumors: Implications for development of targeted therapeutic monoclonal antibodies. Biologics 4: 163–171 [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lim E., Vaillant F., Wu D., Forrest N., Pal B., Hart A., et al. (2009) Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med 15: 907–913 [DOI] [PubMed] [Google Scholar]
  30. Liu S., Wicha M. (2010) Targeting breast cancer stem cells. J Clin Oncol 28: 4006–4012 [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Liu Z., Turkoz A., Jackson E., Corbo J., Engelbach J., Garbow J., et al. (2011) Notch1 loss of heterozygosity causes vascular tumors and lethal hemorrhage in mice. J Clin Invest 121: 800–808 [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Lowell S., Jones P., Le Roux I., Dunne J., Watt F. (2000) Stimulation of human epidermal differentiation by delta-notch signalling at the boundaries of stem-cell clusters. Curr Biol 10: 491–500 [DOI] [PubMed] [Google Scholar]
  33. Mazzone M., Selfors L., Albeck J., Overholtzer M., Sale S., Carroll D., et al. (2010) Dose-dependent induction of distinct phenotypic responses to Notch pathway activation in mammary epithelial cells. Proc Natl Acad Sci U S A 107: 5012–5017 [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Meurette O., Stylianou S., Rock R., Collu G., Gilmore A., Brennan K. (2009) Notch activation induces Akt signaling via an autocrine loop to prevent apoptosis in breast epithelial cells. Cancer Res 69: 5015–5022 [DOI] [PubMed] [Google Scholar]
  35. Mittal S., Subramanyam D., Dey D., Kumar R., Rangarajan A. (2009) Cooperation of Notch and Ras/MAPK signaling pathways in human breast carcinogenesis. Mol Cancer 8: 128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Moellering R., Cornejo M., Davis T., Del Bianco C., Aster J., Blacklow S., et al. (2009) Direct inhibition of the NOTCH transcription factor complex. Nature 462: 182–188 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Mumm J., Schroeter E., Saxena M., Griesemer A., Tian X., Pan D., et al. (2000) A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Mol Cell 5: 197–206 [DOI] [PubMed] [Google Scholar]
  38. Musse A., Meloty-Kapella L., Weinmaster G. (2012) Notch ligand endocytosis: Mechanistic basis of signaling activity. Semin Cell Dev Biol, in press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. O’Neill C., Urs S., Cinelli C., Lincoln A., Nadeau R., Leon R., et al. (2007) Notch2 signaling induces apoptosis and inhibits human MDA-MB-231 xenograft growth. Am J Pathol 171: 1023–1036 [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Okochi M., Steiner H., Fukumori A., Tanii H., Tomita T., Tanaka T., et al. (2002) Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1. EMBO J 21: 5408–5416 [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Osipo C., Patel P., Rizzo P., Clementz A., Hao L., Golde T., et al. (2008) ErbB-2 inhibition activates Notch-1 and sensitizes breast cancer cells to a gamma-secretase inhibitor. Oncogene 27: 5019–5032 [DOI] [PubMed] [Google Scholar]
  42. Pandya K., Meeke K., Clementz A., Rogowski A., Roberts J., Miele L., et al. (2011) Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence. Br J Cancer 105: 796–806 [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Pannuti A., Foreman K., Rizzo P., Osipo C., Golde T., Osborne B., et al. (2010) Targeting Notch to target cancer stem cells. Clin Cancer Res 16: 3141–3152 [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Parks A., Klueg K., Stout J., Muskavitch M. (2000) Ligand endocytosis drives receptor dissociation and activation in the Notch pathway. Development 127: 1373–1385 [DOI] [PubMed] [Google Scholar]
  45. Parr C., Watkins G., Jiang W. (2004) The possible correlation of Notch-1 and Notch-2 with clinical outcome and tumour clinicopathological parameters in human breast cancer. Int J Mol Med 14: 779–786 [DOI] [PubMed] [Google Scholar]
  46. Pece S., Serresi M., Santolini E., Capra M., Hulleman E., Galimberti V., et al. (2004) Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. J Cell Biol 167: 215–221 [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Pellegrinet L., Rodilla V., Liu Z., Chen S., Koch U., Espinosa L., et al. (2011) Dll1- and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells. Gastroenterology 140: 1230–1240, e1231–1237 [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Prat A., Perou C. (2009) Mammary development meets cancer genomics. Nat Med 15: 842–844 [DOI] [PubMed] [Google Scholar]
  49. Rana N., Haltiwanger R. (2011) Fringe benefits: functional and structural impacts of O-glycosylation on the extracellular domain of Notch receptors. Curr Opin Struct Biol 21: 583–589 [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Rangarajan A., Talora C., Okuyama R., Nicolas M., Mammucari C., Oh H., et al. (2001) Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J 20: 3427–3436 [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Reedijk M., Odorcic S., Chang L., Zhang H., Miller N., McCready D., et al. (2005) High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res 65: 8530–8537 [DOI] [PubMed] [Google Scholar]
  52. Reedijk M., Pinnaduwage D., Dickson B., Mulligan A., Zhang H., Bull S., et al. (2008) JAG1 expression is associated with a basal phenotype and recurrence in lymph node-negative breast cancer. Breast Cancer Res Treat 111: 439–448 [DOI] [PubMed] [Google Scholar]
  53. Rizzo P., Miao H., D’Souza G., Osipo C., Song L., Yun J., et al. (2008) Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches. Cancer Res 68: 5226–5235 [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Robinson D., Kalyana-Sundaram S., Wu Y., Shankar S., Cao X., Ateeq B., et al. (2011) Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer. Nat Med 17: 1646–1651 [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Sahlgren C., Gustafsson M., Jin S., Poellinger L., Lendahl U. (2008) Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci U S A 105: 6392–6397 [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Schwanbeck R., Martini S., Bernoth K., Just U. (2011) The Notch signaling pathway: molecular basis of cell context dependency. Eur J Cell Biol 90: 572–581 [DOI] [PubMed] [Google Scholar]
  57. Stylianou S., Clarke R., Brennan K. (2006) Aberrant activation of notch signaling in human breast cancer. Cancer Res 66: 1517–1525 [DOI] [PubMed] [Google Scholar]
  58. Timmerman L., Grego-Bessa J., Raya A., Bertran E., Perez-Pomares J., Diez J., et al. (2004) Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev 18: 99–115 [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. van Es J., van Gijn M., Riccio O., van den Born M., Vooijs M., Begthel H., et al. (2005) Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435: 959–963 [DOI] [PubMed] [Google Scholar]
  60. van Tetering G., van Diest P., Verlaan I., van der Wall E., Kopan R., Vooijs M. (2009) Metalloprotease ADAM10 is required for Notch1 site 2 cleavage. J Biol Chem 284: 31018–31027 [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Watters J., Cheng C., Majumder P., Wang R., Yalavarthi S., Meeske C., et al. (2009) De novo discovery of a gamma-secretase inhibitor response signature using a novel in vivo breast tumor model. Cancer Res 69: 8949–8957 [DOI] [PubMed] [Google Scholar]
  62. Wu Y., Cain-Hom C., Choy L., Hagenbeek T., de Leon G., Chen Y., et al. (2010) Therapeutic antibody targeting of individual Notch receptors. Nature 464: 1052–1057 [DOI] [PubMed] [Google Scholar]
  63. Yamaguchi N., Oyama T., Ito E., Satoh H., Azuma S., Hayashi M., et al. (2008) NOTCH3 signaling pathway plays crucial roles in the proliferation of ErbB2-negative human breast cancer cells. Cancer Res 68: 1881–1888 [DOI] [PubMed] [Google Scholar]
  64. Yan M., Callahan C., Beyer J., Allamneni K., Zhang G., Ridgway J., et al. (2010) Chronic DLL4 blockade induces vascular neoplasms. Nature 463: E6–E7 [DOI] [PubMed] [Google Scholar]
  65. Yang L., Nichols J., Yao C., Manilay J., Robey E., Weinmaster G. (2005) Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1. Mol Biol Cell 16: 927–942 [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Yao K., Rizzo P., Rajan P., Albain K., Rychlik K., Shah S., et al. (2011) Notch-1 and notch-4 receptors as prognostic markers in breast cancer. Int J Surg Pathol 19: 607–613 [DOI] [PubMed] [Google Scholar]
  67. Zang S., Chen F., Dai J., Guo D., Tse W., Qu X., et al. (2010) RNAi-mediated knockdown of Notch-1 leads to cell growth inhibition and enhanced chemosensitivity in human breast cancer. Oncol Rep 23: 893–899 [DOI] [PubMed] [Google Scholar]
  68. Zardawi S., Zardawi I., McNeil C., Millar E., McLeod D., Morey A., et al. (2010) High Notch1 protein expression is an early event in breast cancer development and is associated with the HER-2 molecular subtype. Histopathology 56: 286–296 [DOI] [PubMed] [Google Scholar]
  69. Zavadil J., Cermak L., Soto-Nieves N., Bottinger E. (2004) Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J 23: 1155–1165 [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Zeng Q., Li S., Chepeha D., Giordano T., Li J., Zhang H., et al. (2005) Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell 8: 13–23 [DOI] [PubMed] [Google Scholar]

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