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 17 beta-estradiol (E2) increased the level of TGF alpha mRNA and decreased the level of TGF beta 2 mRNA. TGF beta 1 and TGF beta 3 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 TGF alpha and TGF beta 2 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 TGF alpha and a decrease in TGF beta 2 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 TGF beta 1 and TGF beta 3 gene regulation by E2.
Jeng
M H
MH
Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, Madison 53792.
Jiang
S Y
SY
Jordan
V C
VC
D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism*; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D008233:Lymphotoxin-alpha; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol; C051781:ICI 164384