Cell-cell adhesion is a primary modulator of morphogenesis in embryonic development and cancer. Metastatic dissemination of carcinoma cells is regulated by cell-cell adhesion involving the cadherin family. My laboratory has shown that Neural (N)-cadherin upregulation in breast cancer cells promotes invasion and metastasis due to a cooperative interaction with the fibroblast growth factor receptor (FGFR). This results in oncogenic signaling, causing epithelial to mesenchymal transition (EMT), cancer stemness, and resistance to apoptosis. Specifically, we showed that N-cadherin/FGFR upregulates the EMT-TF, Slug, which in turn promotes cancer cell survival by suppressing the pro-apoptotic protein, Puma. We further showed that N-cadherin suppresses Akt3 to stimulate cell motility, and in the process, we uncovered a tumor suppressive Akt3 isoform, which lacks the regulatory Ser472 phosphorylation site, underscoring the ambiguous effects of Akt3 on breast cancer.  In search of metastasis regulatory pathways, we showed that N-cadherin upregulates the cell cycle inhibitor, p21CIP1, which in turn promotes metastasis by inducing tumor stemness via activation of canonical Wnt/TCF1 signaling.  A recent study in our laboratory elaborates on an intricate mechanism linking TCF1 to the activation of FOXC2, thereby leading to EMT dynamics and metastatic spread.  Lastly, we are investigating the role of redox signaling in metastasis. We showed that the loss of the ROS scavenging enzyme, glutathione peroxidase 2 (GPx2), which is associated with worse clinical outcomes in breast cancer, dramatically enhances metastasis via activation of hypoxia, resulting in EMT and metabolic reprogramming. Using single cell RNA sequencing of the primary tumor and distant metastases, we uncovered novel pathways of metastasis with insights into therapeutic application. Hence, our work has the potential to lead to breakthroughs and accelerate progress towards ending breast cancer. 

Lab members

Kimita Suyama, PhD
Associate
kimita.suyama@einsteinmed.edu

718.430.3374

Outhiriaradjou Benard, PhD

outhiriaradjou.benard@einsteinmed.edu

718.430.3374

Huizhi Liang, PhD
Post-doctoral fellow
Huizhi.liang @einsteinmed.edu
718.430.3374

Viney Kumar, PhD.

Post-doctoral fellow

Viney.kumar @einsteinmed.edu

718.430.3374

Selected Publications

      Suyama K, Shapiro I, Guttman M and Hazan, RB (2002) A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor. Cancer Cell. 2: 301-314. PMID: 12398894

            Hulit et al; Hazan RB (2007). N-cadherin signaling potentiates mammary tumor metastasis via enhanced ERK activation. Cancer Research. 67:3106-16.   

     Agiostratidou G, et al; Hazan RB (2009). Loss of R-cadherin facilitates breast tumor progression and metastasis. Cancer Research. 69:5030-38

     Chung, S., et al; Hazan. R.B. (2013).  N-cadherin promotes breast cancer cell migration through Akt3 suppression. Oncogene. 32(4): 422-30. PMID: 22410780

     Qian, X., et al; Hazan. R.B. (2013). p21 CIP1 mediates reciprocal switching between proliferation and invasion during metastasis. Oncogene.  2012 Jul 2.  PMID: 22751124

     Qian X, et al; Hazan RB. (2014). N-cadherin/FGFR Signaling Promotes Epithelial to Mesenchymal Transition and Tumor Initiating Potential in ErbB2-driven Breast Cancer. Oncogene. PMID: 23975425

     Kim S, et al; Hazan RB. (2014).  Slug Promotes Survival during Metastasis through Suppression of Puma-Mediated Apoptosis. Cancer Research. PMID: 2483072

     Suyama K, et al; and Hazan RB. (2017) an Akt3 splice variant lacking the serine 472 phosphorylation site promotes apoptosis and suppresses mammary tumorigenesis. Cancer Research.  PMID: 29038347

     Benard O, et al; Hazan RB (2019).  p21 CIP1 promotes mammary cancer initiating cells via activation of Wnt/TCF1/Cyclin D1 signaling. Mol Cancer Res. 2019.PMID: 30967481 

     Ren Z, et al; Hazan RB (2021)^. Redox signaling by Glutathione Peroxidase 2 links vascular modulation to metabolic plasticity of breast cancer Proc Natl Acad Sci U S A. 119(8). PMID: 35193955.

Ren Z, et al; Hazan RB (2021)^. Redox signaling by Glutathione Peroxidase 2 links vascular modulation to metabolic plasticity of breast cancer Proc Natl Acad Sci U S A. 119(8). PMID: 35193955.

^.Ren Z, et al; Hazan RB (2023  )Redox signaling regulates breast cancer metastasis via phenotypic and metabolic reprogramming due to HIF1a and p63 activation. British Journal of Cancer (resubmitted).

 Liang H; al; Hazan RB (2023)^. TCF1 orchestrates the partial EMT program in basal-like breast cancer via a FOXC2-p63 axis leading to stemness and metastasis”