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Notch-EGFR/HER2 Bidirectional Crosstalk in Breast Cancer.

Baker AT, Zlobin A, Osipo C - Front Oncol (2014)

Bottom Line: An interesting form of crosstalk exists between the Notch receptor and the Epidermal Growth Factor Receptor Tyrosine Kinase family, which consists of HER-1, -2, -3, and -4.Overexpression of HER and/or Notch occurs in several human cancers including brain, lung, breast, ovary, and skin making them potent oncogenes capable of advancing malignant disease.This review will focus on the current state of crosstalk between the HER and Notch receptors and the effectiveness of current therapies targeting HER-driven cancers.

View Article: PubMed Central - PubMed

Affiliation: Integrative Cell Biology Program, Health Sciences Division, Cardinal Bernardin Cancer Center, Loyola University Chicago , Maywood, IL , USA.

ABSTRACT
The Notch pathway is a well-established mediator of cell-cell communication that plays a critical role in stem cell survival, self-renewal, cell fate decisions, tumorigenesis, invasion, metastasis, and drug resistance in a variety of cancers. An interesting form of crosstalk exists between the Notch receptor and the Epidermal Growth Factor Receptor Tyrosine Kinase family, which consists of HER-1, -2, -3, and -4. Overexpression of HER and/or Notch occurs in several human cancers including brain, lung, breast, ovary, and skin making them potent oncogenes capable of advancing malignant disease. Continued assessment of interplay between these two critical signaling networks uncovers new insight into mechanisms used by HER-driven cancer cells to exploit Notch as a compensatory pathway. The compensatory Notch pathway maintains HER-induced downstream signals transmitted to pathways such as Mitogen Activated Protein Kinase and Phosphatidylinositol 3-Kinase (PI3K), thereby allowing cancer cells to survive molecular targeted therapies, undergo epithelial to mesenchymal transitioning, and increase cellular invasion. Uncovering the critical crosstalk between the HER and Notch pathways can lead to improved screening for the expression of these oncogenes enabling patients to optimize their personal treatment options and predict potential treatment resistance. This review will focus on the current state of crosstalk between the HER and Notch receptors and the effectiveness of current therapies targeting HER-driven cancers.

No MeSH data available.


Related in: MedlinePlus

Notch–HER2 crosstalk in HER2+ DCIS. Farnie et al. discerned a form of Notch–EGFR/HER2 bidirectional communication in an in vitro DCIS breast cancer model that promoted acinar size and mammosphere (BCSC) formation. Dual inhibition of the Notch–EGFR/HER2 receptors using DAPT (GSI) and gefitinib/lapatinib, respectfully, caused decreased acinar size and mammosphere formation while either inhibitor alone effected only acinar size or only mammosphere formation.
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Figure 5: Notch–HER2 crosstalk in HER2+ DCIS. Farnie et al. discerned a form of Notch–EGFR/HER2 bidirectional communication in an in vitro DCIS breast cancer model that promoted acinar size and mammosphere (BCSC) formation. Dual inhibition of the Notch–EGFR/HER2 receptors using DAPT (GSI) and gefitinib/lapatinib, respectfully, caused decreased acinar size and mammosphere formation while either inhibitor alone effected only acinar size or only mammosphere formation.

Mentions: Combined inhibition of Notch and HER pathways, EGFR or HER2 via gefitinib or lapatinib, respectively has been investigated in a DCIS model by Farnie et al. to deduce the effects of dual inhibition of the Notch–EGFR/HER2 pathways on DCIS stem cells (109). Using a 3D culture system to assess luminal filling of DCIS acini as well as DCIS Cancer Stem Cell (CSC) activity, two DCIS cells lines, SUM225 (HER2−), and MCF10DCIS HER2 (HER2+), as well as human primary DCIS samples (HER2±) were studied. These two cell lines were treated with GSI (DAPT) and/or anti-HER1/2 (gefitinib or lapatinib) therapies to deduce the role of Notch–EGFR/HER2 crosstalk in HER± DCIS breast cancer. Anti-Notch treatment reduced mammosphere formation and acini size in the HER2+ cells yet had no effect on the HER2− cells. Anti-EGFR/HER2 treatment had the opposite effect by reducing mammosphere formation and acini size on HER2− cells with no effect on the HER2+ cells. Interestingly, combined inhibition of the Notch and EGFR/HER2 receptors reduced both acini size and mammosphere formation regardless of HER2 expression indicating that the crosstalk between Notch and EGFR/HER2 receptors maintains BCSC survival and self-renewal (Figure 5). In addition to these studies, others have shown that HER2 may facilitate increased expression of components of the Notch pathway such as Notch-ligands (Jag-1, Jag-2, DLL-1) or Notch activating metalloproteinases (ADAM, presenilin-1).


Notch-EGFR/HER2 Bidirectional Crosstalk in Breast Cancer.

Baker AT, Zlobin A, Osipo C - Front Oncol (2014)

Notch–HER2 crosstalk in HER2+ DCIS. Farnie et al. discerned a form of Notch–EGFR/HER2 bidirectional communication in an in vitro DCIS breast cancer model that promoted acinar size and mammosphere (BCSC) formation. Dual inhibition of the Notch–EGFR/HER2 receptors using DAPT (GSI) and gefitinib/lapatinib, respectfully, caused decreased acinar size and mammosphere formation while either inhibitor alone effected only acinar size or only mammosphere formation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4264417&req=5

Figure 5: Notch–HER2 crosstalk in HER2+ DCIS. Farnie et al. discerned a form of Notch–EGFR/HER2 bidirectional communication in an in vitro DCIS breast cancer model that promoted acinar size and mammosphere (BCSC) formation. Dual inhibition of the Notch–EGFR/HER2 receptors using DAPT (GSI) and gefitinib/lapatinib, respectfully, caused decreased acinar size and mammosphere formation while either inhibitor alone effected only acinar size or only mammosphere formation.
Mentions: Combined inhibition of Notch and HER pathways, EGFR or HER2 via gefitinib or lapatinib, respectively has been investigated in a DCIS model by Farnie et al. to deduce the effects of dual inhibition of the Notch–EGFR/HER2 pathways on DCIS stem cells (109). Using a 3D culture system to assess luminal filling of DCIS acini as well as DCIS Cancer Stem Cell (CSC) activity, two DCIS cells lines, SUM225 (HER2−), and MCF10DCIS HER2 (HER2+), as well as human primary DCIS samples (HER2±) were studied. These two cell lines were treated with GSI (DAPT) and/or anti-HER1/2 (gefitinib or lapatinib) therapies to deduce the role of Notch–EGFR/HER2 crosstalk in HER± DCIS breast cancer. Anti-Notch treatment reduced mammosphere formation and acini size in the HER2+ cells yet had no effect on the HER2− cells. Anti-EGFR/HER2 treatment had the opposite effect by reducing mammosphere formation and acini size on HER2− cells with no effect on the HER2+ cells. Interestingly, combined inhibition of the Notch and EGFR/HER2 receptors reduced both acini size and mammosphere formation regardless of HER2 expression indicating that the crosstalk between Notch and EGFR/HER2 receptors maintains BCSC survival and self-renewal (Figure 5). In addition to these studies, others have shown that HER2 may facilitate increased expression of components of the Notch pathway such as Notch-ligands (Jag-1, Jag-2, DLL-1) or Notch activating metalloproteinases (ADAM, presenilin-1).

Bottom Line: An interesting form of crosstalk exists between the Notch receptor and the Epidermal Growth Factor Receptor Tyrosine Kinase family, which consists of HER-1, -2, -3, and -4.Overexpression of HER and/or Notch occurs in several human cancers including brain, lung, breast, ovary, and skin making them potent oncogenes capable of advancing malignant disease.This review will focus on the current state of crosstalk between the HER and Notch receptors and the effectiveness of current therapies targeting HER-driven cancers.

View Article: PubMed Central - PubMed

Affiliation: Integrative Cell Biology Program, Health Sciences Division, Cardinal Bernardin Cancer Center, Loyola University Chicago , Maywood, IL , USA.

ABSTRACT
The Notch pathway is a well-established mediator of cell-cell communication that plays a critical role in stem cell survival, self-renewal, cell fate decisions, tumorigenesis, invasion, metastasis, and drug resistance in a variety of cancers. An interesting form of crosstalk exists between the Notch receptor and the Epidermal Growth Factor Receptor Tyrosine Kinase family, which consists of HER-1, -2, -3, and -4. Overexpression of HER and/or Notch occurs in several human cancers including brain, lung, breast, ovary, and skin making them potent oncogenes capable of advancing malignant disease. Continued assessment of interplay between these two critical signaling networks uncovers new insight into mechanisms used by HER-driven cancer cells to exploit Notch as a compensatory pathway. The compensatory Notch pathway maintains HER-induced downstream signals transmitted to pathways such as Mitogen Activated Protein Kinase and Phosphatidylinositol 3-Kinase (PI3K), thereby allowing cancer cells to survive molecular targeted therapies, undergo epithelial to mesenchymal transitioning, and increase cellular invasion. Uncovering the critical crosstalk between the HER and Notch pathways can lead to improved screening for the expression of these oncogenes enabling patients to optimize their personal treatment options and predict potential treatment resistance. This review will focus on the current state of crosstalk between the HER and Notch receptors and the effectiveness of current therapies targeting HER-driven cancers.

No MeSH data available.


Related in: MedlinePlus