Abstract
Aberrant Notch signaling can induce mammary gland carcinoma in transgenic mice, and high expressions of Notch receptors and ligands have been linked to poor clinical outcomes in human patients with breast cancer. This suggests that inhibition of Notch signaling may be beneficial for breast cancer treatment. In this review, we critically evaluate the evidence that supports or challenges the hypothesis that inhibition of Notch signaling would be advantageous in breast cancer management. We find that there are many remaining uncertainties that must be addressed experimentally if we are to exploit inhibition of Notch signaling as a treatment approach in breast cancer. Nonetheless, Notch inhibition, in combination with other therapies, is a promising avenue for future management of breast cancer. Furthermore, since aberrant Notch4 activity can induce mammary gland carcinoma in the absence of RBPjκ, a better understanding of the components of RBPjκ-independent oncogenic Notch signaling pathways and their contribution to Notch-induced tumorigenesis would facilitate the deployment of Notch inhibition strategies for effective treatment of breast cancer.
Highlights
Notch signaling is an evolutionarily conserved pathway that is essential for embryonic development, organogenesis, and tissue homeostasis
Transgenic mice expressing constitutively active N1ICD or N3ICD in mammary epithelium were shown to develop mammary gland carcinomas [4]. These observations, together with the report that high expression of Jagged1, a Notch ligand, or Notch1 which likely leads to elevated Notch signaling is associated with poor clinical outcomes [5], have stimulated intense interest in exploring Notch signaling as a therapeutic target for breast cancer treatment
There are several indirect lines of evidence that support our hypothesis: (a) the dose-dependent nature of the transformation potential of activating Notch1 mutant alleles in T-cell acute lymphoblastic leukemia (T-ALL) might reflect the fact that the N1ICD level needs to reach a threshold above which N1ICD could activate several non-canonical Notch signaling pathways by forming novel Notch intracellular domain (NICD) protein complexes; (b) NICDs have been reported to associate with NFκB, IKKα, Smad3, HIF1α, YY1, and JNK, all of which have been implicated in oncogenesis and cancer cell survival [45,47,48]; and (c) inhibition of NFκB activity delayed the onset of N1ICD-induced oncogenesis of T-ALL [52]
Summary
Notch signaling is an evolutionarily conserved pathway that is essential for embryonic development, organogenesis, and tissue homeostasis. There are several indirect lines of evidence that support our hypothesis: (a) the dose-dependent nature of the transformation potential of activating Notch mutant alleles in T-ALL might reflect the fact that the N1ICD level needs to reach a threshold above which N1ICD could activate several non-canonical Notch signaling pathways by forming novel NICD protein complexes; (b) NICDs have been reported to associate with NFκB, IKKα, Smad, HIF1α, YY1, and JNK, all of which have been implicated in oncogenesis and cancer cell survival [45,47,48]; and (c) inhibition of NFκB activity delayed the onset of N1ICD-induced oncogenesis of T-ALL [52]. A better understanding of the components of RBPjκ-independent oncogenic Notch signaling pathways and their contribution to Notch-induced tumorigenesis would help us to develop new strategies to treat Notchdependent cancers
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