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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.

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Combining Notch inhibition with current therapies for breast cancer treatment

Abstract

Keywords

Aberrant activation of Notch signalling in breast cancer

Notch signalling alters many cellular properties in breast cancer

Many ways to inhibit the Notch pathway

Notch pathway inhibitors are unlikely to be useful as a monotherapy

Notch pathways inhibitors increase the effectiveness of current therapies

Conclusion

Footnotes

Funding

Conflict of interest statement

References