Evidence that transforming growth factor-β is a hormonally regulated negative growth factor in human breast cancer cells

Knabbe, Cornelius; Lippman, Marc E.; Wakefield, Lalage M.; Flanders, Kathleen C.; Kasid, Attan; Derynck, Rik; Dickson, Robert B.

doi:10.1016/0092-8674(87)90193-0

Cited by 904 publications

(368 citation statements)

References 31 publications

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“…Aberrant stromal phenotypes in breast tumours may lead to deranged stromal -epithelial interactions and promote neoplastic progression. Increased synthesis of TGF-/31 is not associated with any concomitant elevation of mRNA levels in MCF-7 breast cancer cells (Knabbe et al, 1987) or fetal fibroblasts (Colletta et al, 1990). We have similar data from breast tumour fibroblasts in vitro (data not shown), and tamoxifen would therefore appear to enhance synthesis at a post-transcriptional level, although transcriptional mechanisms may also be operative depending on the local tissue levels of tamoxifen (Perry et al, 1995;Benson and Baum, 1996) and TGF-# isoform type (Arrick et al, 1994;MacCallum et al, 1994).…”

Section: Secretion Of Tgf-f3 Isoforms Into Conditioned Media Of Fibromentioning

confidence: 99%

Synthesis and secretion of transforming growth factor beta isoforms by primary cultures of human breast tumour fibroblasts in vitro and their modulation by tamoxifen

Benson

Wakefield²,

Baum³

et al. 1996

Br J Cancer

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Summary Tamoxifen may mediate its effect in early breast cancer in part via an oestrogen receptor (ER)-independent pathway by directly stimulating fibroblasts to produce the negative paracrine growth factor transforming growth factor (TGF)-f,. We have previously shown that secretion of this factor is induced 3-to 30-fold in human fetal fibroblasts in vitro, and by stromal fibroblasts in vivo following tamoxifen treatment of ERpositive and ER-negative breast cancer patients. Primary cultures of breast tumour fibroblasts have been exposed to tamoxifen for 48 h, and rates of secretion of TGF-fl, and TGF-fl2 measured using a quantitative immunoassay. Fibroblast strains derived from malignant and benign tumours produced and secreted similar amounts of TGF-flp, but benign breast tumour fibroblasts secreted significantly higher levels of TGF-f32 compared with fibroblasts of malignant origin. Tamoxifen did not induce any consistent increase in TGF-,B secretion into the conditioned medium, but immunofluorescence analysis for the intracellular form of TGF-f3, revealed evidence of increased immunoreactive protein in tamoxifen-treated fibroblasts, which is localised to the nucleus. Therefore synthesis of TGF-fl, appears to be stimulated by tamoxifen, but increased secretion may be abrogated in vitro. Furthermore, using immunocytochemistry and transient transfection with an ER-responsive reporter construct, no ER was demonstrable in these fibroblasts supporting the proposed ER-independent paracrine pathway.

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Section: Secretion Of Tgf-f3 Isoforms Into Conditioned Media Of Fibromentioning

confidence: 99%

Synthesis and secretion of transforming growth factor beta isoforms by primary cultures of human breast tumour fibroblasts in vitro and their modulation by tamoxifen

Benson

Wakefield²,

Baum³

et al. 1996

Br J Cancer

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“…It has, however, become increasingly apparent that many biological activities of tamoxifen are potentiated in a manner divorced from estrogen receptor machinery [3]. Examples of activities promoted by tamoxifen include protection against lipid peroxidation [4], induction of transforming growth factor-[3 [5], modification of protein kinase C activity [6 8], activation of lipid second messenger signaling [9], and antagonism of calmodulin [10]. Along these lines, the utility of tamoxifen in non-breast related disease, e.g.…”

Section: Introductionmentioning

confidence: 99%

Tamoxifen retards glycosphingolipid metabolism in human cancer cells

et al. 1996

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In this study we provide evidence that tamoxifen, the widely used breast cancer drug, is a potent antagonist of glycolipid metabolism. When added to the medium of cultured multidrug resistant (MDR) KB-V-I carcinoma cells, tamoxifen, at 5.0 pM, drastically lowered the levels of glucosylceramide (glc-cer), as evidenced by a reduction in glc-cer mass. In a similar fashion, in cultured human melanoma cells grown with [3H]galactose, tamoxifen inhibited formation of glc-cer by 44%, and retarded lactosylceramide and ganglioside formation by 50 and 35%, respectively. When glc-cer synthase of melanoma was assayed in cell-free incubations, the inclusion of tamoxifen, at a I :I0 molar ratio with ceramide, inhibited glc-cer synthesis by 50%. These results clearly reveal a new action of tamoxifen and thereby pose intriguing questions regarding mechanisms of action in the realm of estrogen receptor-independent modalities, including effects on MDR.

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“…The roles of ER are known to act not only as a steroid hormone nuclear receptor but also as a cell surface receptor linked to several intracellular mitogen-activated protein kinase (MAPK) pathways. [7][8][9][10][11][12] Other non-ER-mediated mechanisms of TAM effects on antiproliferation have been suggested to induce transforming growth factor-beta (TGF-␤) synthesis, 13 lower the circulating levels of insulin-like growth factor-1 (IGF-1), 14 and inhibit the protein kinase C (PKC) pathways. 15 All-trans retinoic acid (RA) binds and activates the nuclear RAR, which reveals a striking homology to the steroid receptor and acts as a transcriptional factor.…”

mentioning

confidence: 99%

Resistance to tamoxifen‐induced apoptosis is associated with direct interaction between Her2/neu and cell membrane estrogen receptor in breast cancer

Chung

Sheu

Yang

et al. 2001

Intl Journal of Cancer

123

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Overexpression of Her2/neu is implicated in the development of resistance to the antiestrogen tamoxifen (TAM) that exerts its inhibitory effect through interaction with estrogen receptor (ER). Whereas Her2/neu and ER are believed to be important cell survival/death factors in human breast cancer cells, if and how they interact to confer resistance to hormone therapy is not known. This prompted us to investigate whether modulation of the effect of TAM occurs via the Her2/neu pathway and whether targeting the interaction between the Her2/neu pathway and the ER pathway is beneficial. There are 2 forms of ER that are localized to the cell membrane and to the nucleus. For the first time, we found that Her2/neu directly interacts with ER at the cell membrane. We then investigated the role of Her2/neu overexpression in the regulation of the cell membrane ER pathway in TAM-resistant breast cancer cells and the nature of this interaction in apoptotic signaling. Relief of TAM resistance was associated with Her2/neu downregulation and ER upregulation. TAM-induced apoptosis occurred immediately after dissociation of Her2/neu from cell membrane ER. These results demonstrate a novel mechanism by which Her2/neu regulates the cell membrane ER-coupled apoptosis and the possible involvement of the Her2/neu in TAM resistance of breast cancer cells. Moreover, the antiproliferative activity of TAM should rely on the integration between the signal transduction from the cell membrane ER and the gene regulation by the nuclear ER. Coordinated modulation on the cell membrane ER/Her2/neu pathway and the nuclear ER/RAR pathway may provide a new approach for treatment of ER-positive, Her2/neu overexpressing breast cancer.

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Evidence that transforming growth factor-β is a hormonally regulated negative growth factor in human breast cancer cells

Cited by 904 publications

References 31 publications

Synthesis and secretion of transforming growth factor beta isoforms by primary cultures of human breast tumour fibroblasts in vitro and their modulation by tamoxifen

Synthesis and secretion of transforming growth factor beta isoforms by primary cultures of human breast tumour fibroblasts in vitro and their modulation by tamoxifen

Tamoxifen retards glycosphingolipid metabolism in human cancer cells

Resistance to tamoxifen‐induced apoptosis is associated with direct interaction between Her2/neu and cell membrane estrogen receptor in breast cancer

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