**5. Other receptors involved in breast cancer**

## **5.1. NOTCH signaling pathway**

Notch signaling pathway within the breast cancer field attracted a huge number of research scientists over the past decade. It has been observed that Notch signaling is aberrantly activated in breast cancer and affects a number of cellular processes such as apoptosis, proliferation and cancer stem cell activity. The Notch signaling pathway consists of four receptors (Notch1, Notch2, Notch3 and Notch4) and five Delta/Serrate/LAG-2 (DSL) ligands Jagged1, Jagged2, Delta-like1 (Dll1, Dll3 and Dll4). The activation of Notch signaling pathway occurs by the interaction of DSL ligands with Notch receptors on adjacent cells. This interaction induces a proteolytic cleavage of the Notch protein at the S2 cleavage site mediated by two enzymes, Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) and Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). After this cleavage, the remaining part of the Notch protein will be cleaved by the γ-secretase enzyme complex and releases the Notch intracellular domain (NICD). Finally, NICD translocates to the nucleus and forms a complex with DNA-binding protein recombination signal binding protein for immunoglobulin Kappa J region (RBPj) and a member of the mastermindlike (MAML) family transcriptional coactivators (**Figure 4**). This complex activates various target genes of Notch pathway that are associated with tumorigenesis [42], cell growth, differentiation, and cell survival [43].

A number of studies indicate that aberrant activation of Notch signaling has been observed in breast cancer. The high expression of Notch signaling pathway components including Dll1, Dll3 and Dll4, Jagged1–2 and Notch receptors has been observed in invasive breast cancer. This expression is associated with poor prognosis in breast cancer patients [43, 44]. Due to the important role of Notch signaling pathway in breast cancer, it becomes a very attractive therapeutic target. At present, several classes of Notch inhibitors have been developed and are under various clinical trials including γ-secretase inhibitor (GSI), monoclonal antibodies against Notch receptors or ligands and small interfering RNA (siRNA).GSI effectively represses cancer stem cells (CSCs) in *in vitro* studies and triggers apoptosis via inhibiting proteasome activity and enhancing endoplasmic reticulum (ER) stress in tumor cells [45]. Several GSIs have completed pre-clinical and early clinical trials including RO4929097 which significantly sensitizes putative breast cancer stem cells to ionizing radiation and may be effective in treating inflammatory breast cancer (IBC), MRK-003 in combination with trastuzumab induced tumor regression and prevented tumor recurrence post-trastuzumab

**Figure 4.** Basics of notch signaling pathway. Modified from Acar et al. [42].

transducer and activator of transcription protein 3 (STAT3) has been associated with trastuzumab resistance. This suggests that STAT3 acts as a prognostic indicator of trastuzumab resistance in primary HER2-positive breast cancer [39]. More than 50% of breast cancer patients with aggressive and chemotherapeutic resistant condition have been detected with the phosphorylation of STAT3. Abnormal STAT3 activation due to alterations in HER2, HER1, BRCA1, and ER leads to deregulation of cell proliferation, migration, survival and angiogenesis. Several up-regulated genes including hypoxia inducible factor 1 alpha (HIF-1α) as a result of unexpected STAT3 activation have been implicated in trastuzumab resistance. During their study, Aghazadeh and Yazdanparast found that HIF-1α is an essential signaling element required to downregulate phosphatase and tensin homolog (PTEN) via Hes Family BHLH Transcription Factor 1 (HES-1) repressor during the induction of trastuzumab resistance [39]. Similarly, Sonnenblick et al. provide convincing evidence for a link between phosphorylation of STAT3 and trastuzumab resistance in HER2 positive primary breast cancers. Patients with activated STAT3 may suggest novel approaches to block the STAT3 pathway in combination with trastuzumab treatment particularly in PTEN-deleted breast cancer [40]. Additionally, it has been observed that inhibition of IL6-STAT3 pathway in PTEN-deleted HER2 positive breast cancer leads to decrease in the population of cancer stem cells and inhibits the development of dis-

**Figure 3.** TKIs and MAbs target HERs for the treatment of breast, lung and several other types of cancer. Modified from

tance metastasis using IL6R antibody alone or in combination with trastuzumab [41].

Notch signaling pathway within the breast cancer field attracted a huge number of research scientists over the past decade. It has been observed that Notch signaling is aberrantly activated in breast cancer and affects a number of cellular processes such as apoptosis, proliferation and cancer stem cell activity. The Notch signaling pathway consists of four receptors (Notch1, Notch2, Notch3 and Notch4) and five Delta/Serrate/LAG-2 (DSL) ligands Jagged1,

**5. Other receptors involved in breast cancer**

**5.1. NOTCH signaling pathway**

Alanazi and Khan [16].

114 Breast Cancer and Surgery

treatment in HER2 positive breast xenografts and partially reverses trastuzumab resistance *in vivo*, MK-0752 reduced breast cancer stem cell subpopulation *in vitro* and in human tissues and PF-03084014 exhibited antitumor and antimetastatic activity in breast xenograft models (**Table 3**) [45].
