Paradoxical regulation of estrogen-dependent growth factor gene expression in estrogen receptor (ER)-negative human breast cancer cells stably expressing ER

We have previously demonstrated that transfection of estrogen receptor (ER)-negative human breast cancer MDA-MB-231 (clone 10A) cells with a sense constitutive wildtype ER expression vector regains hormonal responsiveness (Jiang and Jordan, J. Natl. Cancer Inst., 84 (1992) 580-591). We have therefore undertaken studies using stable transfectant S30 cells to determine the function of ER in the regulation of the levels of growth factor mRNAs, an event believed to be mediated via the ER and is important for the paracrine and autocrine regulation of breast cancer cell proliferation. Northern blot analysis demonstrated that 17β-estradiol (E₂) increased the level of TGFα mRNA and decreased the level of TGFβ2 mRNA. TGFβ1 and TGFβ3 mRNA levels were not affected by ER in S30 cells. The addition of anti-estrogen ICI 164,384 blocked the regulation of the mRNA levels of TGFα and TGFβ2 by E2. The expression of these growth factor mRNAs was not affected by E₂ or ICI 164,384 in the parental MDA-MB-231 10A and antisense ER transfectant AS23 cells. We demonstrated that the expression of ER in previously ER-negative human breast cancer cells can restore the regulation of growth factor mRNA expression by E₂. An increase in TGFα and a decrease in TGFβ2 is associated with an increase in growth of hormone responsive cells. Paradoxically the transfected cells have decreased growth in response to estrogen. Furthermore, these data suggest that other factors in addition to ER are required for TGFβ1 and TGFβ3 gene regulation by E₂.