title: Role of the EphB2 receptor in autophagy, apoptosis and invasion in human breast cancer cells.
abstract: The Eph and Ephrin proteins, which constitute the largest family of receptor tyrosine kinases, are involved in normal tissue development and cancer progression. Here, we examined the expression and role of the B-type Eph receptor EphB2 in breast cancers. By immunohistochemistry using a progression tissue microarray of human clinical samples, we found EphB2 to be expressed in benign tissues, but strongly increased in cancers particularly in invasive and metastatic carcinomas. Subsequently, we found evidence that EphB2, whose expression varies in established cell breast lines, possesses multiple functions. First, the use of a DOX-inducible system to restore EphB2 function to low expressers resulted in decreased tumor growth in vitro and in vivo, while its siRNA-mediated silencing in high expressers increased growth. This function involves the onset of apoptotic death paralleled by caspases 3 and 9 activation. Second, EphB2 was also found to induce autophagy, as assessed by immunofluorescence and/or immunoblotting examination of the LC3, ATG5 and ATG12 markers. Third, EphB2 also has a pro-invasive function in breast cancer cells that involves the regulation of MMP2 and MMP9 metalloproteases and can be blocked by treatment with respective neutralizing antibodies. Furthermore, EphB2-induced invasion is kinase-dependent and is impeded in cells expressing a kinase-dead mutant EphB2. In summary, we identified a mechanism involving a triple role for EphB2 in breast cancer progression, whereby it regulates apoptosis, autophagy, and invasion.
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Sahiti
authors.initials: S
authors.lastname: Chukkapalli
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Amessou
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Dilly
authors.affiliation: Obesity Research Center, College of Medicine, King Saud University, Kingdom of Saudi Arabia.
authors.forename: Hafedh
authors.initials: H
authors.lastname: Dekhil
authors.affiliation: Montréal Centre for Experimental Therapeutics in Cancer, Segal cancer Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Montréal Centre for Experimental Therapeutics in Cancer, Segal cancer Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Bejna
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Ron D
authors.initials: RD
authors.lastname: Thomas
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Sudeshna
authors.initials: S
authors.lastname: Bandyopadhyay
authors.affiliation: Departments of Pathology & Laboratory Medicine, Oncology, Biochemistry & Molecular Biology, University of Calgary, Calgary, Canada.
authors.forename: Tarek A
authors.initials: TA
authors.lastname: Bismar
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Neill
authors.affiliation: Department of Oncology, McGill University, Montréal, Québec, Canada.
authors.forename: Laurent
authors.initials: L
authors.lastname: Azoulay
authors.affiliation: Montréal Centre for Experimental Therapeutics in Cancer, Segal cancer Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada; Department of Oncology, McGill University, Montréal, Québec, Canada.
authors.forename: Gerald
authors.initials: G
authors.lastname: Batist
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, MI, USA; Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA. Electronic address: ag1764@wayne.edu.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Kandouz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001343:Autophagy / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002478:Cells, Cultured; D018450:Disease Progression; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D036183:Receptor, EphB2 / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: C586310:EPHB2 protein, human; D036183:Receptor, EphB2
keywords: Apoptosis; Autophagy; B-type Eph receptor 2; Breast cancer; DOX; EphB2; Ephrin; Invasion; MMP; RTK; TMA; doxycycline; matrix metalloproteinase; receptor tyrosine kinases; tissue microarray