To ascertain if 17β‐estradiol (E2)‐induced proliferation could be attenuated by blocking the expression of endogenous transforming growth factor α (TGFα), estrogen receptor (ER)‐positive, estrogen‐responsive MCF‐7 or ZR‐75‐1 cells and ER‐negative, estrogen‐nonresponsive MDA‐MB‐468 or HS‐578T cells were infected with a recombinant amphotropic, replication‐defective retroviral expression vector containing a 435 base pair (bp) Apa1‐Eco R1 coding fragment of the human TGFα cDNA oriented in the 3′ to 5′ direction and under the transcriptional control of an internal heavy metal‐inducible mouse metallothionein (MT‐1) promoter and containing the neomycin (neo) resistance gene. E2‐stimulated expression of endogenous TGFα mRNA was inhibited by 4–5‐fold, and the production of TGFα protein was inhibited by 50–80% when M‐1 mass‐infected MCF‐7 or MZ‐1 mass‐infected ZR‐75‐1 cells were treated with 0.75‐1 μM CdCl2, whereas in comparably treated parental MCF–7 or ZR‐75‐1 cells there was no significant effect upon these parameters. E2‐stimulated anchorage‐dependent growth (ADG) and anchorage‐independent growth (AIG) of the M‐1 or MZ‐1 cells was inhibited by 60–90% following CdCl2 treatment. In contrast, neither the ADG nor AIG of the parental noninfected MCF‐7 or ZR‐75‐1 cells that were maintained in the absence or presence of E2 was affected by comparable concentrations of CdCl2. The ADG and AIG of TGFα antisense MD‐1 mass‐infected MDA‐MB‐468 cells that express high levels of endogenous TGFα mRNA were also inhibited by 1 μM CdCl2, whereas the ADG and AIG of MH‐1 mass‐infected HS‐578T cells, a TGFα‐negative cell line, were unaffected by CdCl2 treatment. These results suggest that TGFα may be one important autocrine intermediary in regulating estrogen‐induced cell proliferation. © 1993 Wiley‐Liss, Inc.