P. Briand et al., TRISOMY 7P AND MALIGNANT TRANSFORMATION OF HUMAN BREAST EPITHELIAL-CELLS FOLLOWING EPIDERMAL GROWTH-FACTOR WITHDRAWAL, Cancer research, 56(9), 1996, pp. 2039-2044
We have reported previously on the first spontaneously immortalized, n
onmalignant human breast epithelial cell line, HMT-3522, which is enti
rely dependent on exogenous epidermal growth factor (EGF), In passage
118, cells were adapted to grow in medium without EGF and a new growth
-transformed subline, HMT-3522/gt-1, was generated and propagated at h
igh growth rate without exogenous EGF (Madsen et al., Cancer Res., 52:
1210-1217, 1992). Here we have used this subline and the continuum of
the parent line, HMT-3522/wt, to pose the question whether a relevant
change in a physiological parameter of the microenvironment will indu
ce malignant transformation, The two cell lines were cultured under id
entical conditions with the only exception that EGF was omitted in the
medium for gt-1. Initially, wt and gt-l were identical in terms of ka
ryotype as well as morphology, growth rate, and protein expression as
revealed by two-dimensional gel electrophoresis. A highly dramatic shi
ft in phenotype was observed in passage 238 when the gt-l line became
tumorigenic in nude mice, After two mouse-culture passages, the result
ing malignantly transformed cell line (HMT-3522/mt-1) was refractory t
o the growth-modulating effect of EGF and presented an extra copy of a
chromosome marker, 7q-, as the only cytogenetic difference from the g
t-l, Our results suggest that microenvironmental cues are powerful fac
tors in the induction of malignancy, A major role of EGF receptor in t
he malignant transformation is emphasized by loss of EGF sensitivity a
nd acquisition of an extra chromosome 7p harboring the EGF receptor ge
ne, We hypothesize that during premalignant hyperplasia, a population
of EGF/transforming growth factor alpha autonomous epithelial cells in
situ may develop as a consequence of local transforming growth factor
alpha deprivation, a condition reflected in the culture model as auto
nomy after EGF withdrawal.