Inhibition of estrogen-induced breast cancer cell proliferation by reduction in autocrine transforming growth factor α expression

K. B. Reddy, D. Yee, S. G. Hilsenbeck, R. J. Coffey, C. K. Osborne

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Abstract

Breast cancer cell lines have been shown to secrete transforming growth factor α (TGFα) and other polypeptide growth factors in response to estrogen (E2) stimulation. In this study, we investigated whether cellular- derived TGFα mediates the growth-stimulatory effects of E2 in ER-positive breast cancer cells. To test this hypothesis, we introduced an antisense TGFα mRNA expression vector under control of a human metallothionein promoter into E2-responsive T47D human breast cancer cells. In stably transfected cells, cadmium induced antisense mRNA and reduced expression of TGFα mRNA and protein in antisense clones (AS1). TGFα expression was increased in sense clones (S2), while wild-type T47D cells (W3) or pSV2 neomycin resistance-transfected cells showed no change in TGFα expression in response to cadmium. The basal proliferative capacity of antisense transfected cells was equivalent to that of the wild-type. E2 increased TGFα synthesis and cell proliferation in transfected and wild-type cells. In AS1 cells, the simultaneous addition of cadmium with E2 blocked most of the E2-induced increase in TGFα mRNA and protein and nearly abolished the stimulatory effects of E2 on DNA synthesis and cell number. In contrast, no reduction in cell proliferation was observed with cadmium in antisense- transfected cells with a low level of antisense expression or in the S2 or W3 cells. Our results are compatible with the hypothesis that autocrine production of TGFα may be an important contributor to E2-induced growth in T47D cells.

Original languageEnglish (US)
Pages (from-to)1275-1282
Number of pages8
JournalCell Growth and Differentiation
Volume5
Issue number12
StatePublished - 1994

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