טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentTamir Ronit-Rachel
SubjectAnti Tumorigenesis of All-Trans Retinoic-Acid (ATRA) in
Breast Cancer is Mediated by the Inhibition of MIF
and CD44 Expression
DepartmentDepartment of Medicine
Supervisor Professor Shimon Pollack
Full Thesis textFull thesis text - English Version


Abstract

Macrophage Inhibitory Factor (MIF) is a cytokine secreted by various tumor cells and binds to CD44-CD74 MIF receptor complex.  Enhanced cell surface expression of certain CD44 isoforms and increased secretion of MIF are closely correlated with the progression and prognosis of breast cancer.

All-trans retinoic acid (ATRA) and other retinoic acid (RA) compounds modulate cell growth and differentiation, inhibit angiogenesis and thus may have an anti-tumoricidal effect. Both naturally occurring and synthetic retinoids may inhibit breast cancer cells proliferation. In view of these findings, we decided to investigate whether the anti-proliferative effect of ATRA in cancer cell lines may be mediated through an effect on MIF pathway .We tested several cancer cell lines and could find an effect of  ATRA on MIF signaling and secretion only in MCF-7 breast cancer cells.

ATRA treatment of MCF-7 cells resulted in decreased proliferation associated with reduced MIF and VEGF secretion, increased secretion of IL-8 and TGF-β1 and down regulation of CD44 expression. In addition, ATRA treatment was associated also with reduced expression of CD44 in MCF-7 cells but not in other cancer cells. Long-term treatment of MCF-7 cells with ATRA resulted in reduced phosphorylation of Lyn, a src-family tyrosine kinase implicated in the transduction of regulatory signals by CD44. Also, ERK and p38 kinase phosphorylation were affected by ATRA treatment and this was associated with increased secretion of IL-8 and TGF-β1. Blocking of CD44 in MCF-7 cells was associated with reduction of MIF secretion and, to a lesser extent, of VEGF secretion, thus elucidating the role of CD44 in the induction of MIF secretion. Inhibition of ERK alone in ATRA treated MCF-7 cells resulted in the reduction of TGF-β1 secretion whereas inhibition of both ERK and p38 resulted in decreased IL-8 secretion.

We propose that ATRA-induced anti-tumoricidal effect in breast cancer MCF-7 cells is mediated mainly through a reduction of CD44 expression which results in an impairment of the interaction between MIF and CD44. This is leading to a decreased MIF signal transduction which results in reduction of MIF and VEGF production and of MCF-7 tumor cell proliferation. Inhibition of MIF and VEGF secretion together with the stimulation of TGF-β1 secretion may contribute to the anti-proliferative effect of ATRA in breast cancer.