INDUCTION OF APOPTOSIS BY EGF RECEPTOR IN RAT MAMMARY ADENOCARCINOMA CELLS COINCIDES WITH ENHANCED SPONTANEOUS TUMOR-METASTASIS

The low metastatic MTC (13762NF) rat mammary adenocarcinoma cell line is devoid of epidermal growth factor receptor (EGFR). To test for a li nk between expression of EGFR and the ability of tumour cells to metas tasise from their orthotopic site (spontaneous metastasis), stable sub clones of this line (S+) that had been retrovirally transduced to expr ess an ectopic full length HER1 were established and characterised, Pr oliferation, survival, and response to TGF-alpha were investigated and related to the tumorigenic growth and metastatic properties of the ce lls, S+ clones responded in vitro to ligand stimulation by growth inhi bition and apoptosis, Upon orthotopic inoculation into the mammary fat pad of nude (nu/nu) mice, S+ clones showed retarded growth and apopto sed in situ, while MTC cells or neo(R) control cells showed no signs o f apoptosis, Yet, S+ cells exhibited more spontaneous metastasis than the MTC parental cells or neo(R) control cells, Spontaneous metastasis requires cellular detachment (primary site) as well as attachment (se condary site) and growth in target organs, Neither the HER1 mediated i ncreased ECM adhesion nor its negative effect on growth potential expl ains the observed effect, This is the first direct demonstration of th e potential of EGFR to promote spontaneous metastasis of mammary adeno carcinoma cells from their orthotopic site.