Regulation of epidermal growth factor receptor by progestins and glucocorticoids in human breast cancer cell lines

Publisher Website
Google Scholar
Abstract
Human breast cancer cells secrete a number of autocrine peptides which modulate their proliferation rates. The known effects of steroid hormones on breast cancer cell proliferation may be mediated in part by altering the production of these growth factors and/or their interactions with cellular receptor sites. Receptors for epidermal growth factor (EGF), which also bind the autocrine growth factor, α‐transforming growth factor, are present on a number of breast cancer cell lines and it has previously been shown that T‐47D and MCF‐7 cells respond to progestins with an increase in the concentration of EGF receptors (EGF‐R). In the present study we examined the effects of both progestins and glucocorticoids on EGF binding in 10 human breast cell lines. Five of these lines were progesterone receptor positive and all lines expressed the glucocorticoid receptor (GR). All cell lines were initially incubated for 24 hr with increasing concentrations of the synthetic progestin, medroxyprogesterone acetate (MPA), and the level of specifically bound EGF was determined. An increase in specific binding of EGF was confirmed in two PR‐positive lines but, in addition, increases in EGF binding were observed in 4 PR‐negative cell lines. In these last lines the synthetic glucocorticoid, dexamethasone, was a more potent inducer of EGF binding than MPA, a known glucocorticoid agonist, while the high‐affinity PR ligand, ORG 2058, was without effect. Furthermore, MPA competed with dexamethasone for binding to GR in these cell lines, supporting the view that the induction of EGF binding by MPA in these cells was mediated via the GR. This conclusion was further supported by studies in which addition of the glucocorticoid and progestin antagonist, RU 486, inhibited the effect of ORG 2058 in two cell lines and completely abrogated the effect of dexamethasone in two other lines. Detailed binding studies revealed that the increase in EGF binding was accompanied by an increase in the concentration of EGF‐R. This effect was observed when EGF binding was assayed at either 0° or 37°C. Further studies demonstrated that the increases in EGF binding following ORG 2058 and dexamethasone treatment were accompanied by increases in EGF‐R mRNA levels. Our data illustrate that the binding of EGF by some human breast cancer cells can be regulated by both progestins and glucocorticoids acting vía their respective receptors and inducing increases in EGF‐R mRNA levels.