Altered estrogen receptor and transforming growth factor pathways in models of estrogen-autonomous and of antiestrogen-resistant MCF-7 human breast cancer cells
Herman, Mary E.
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Permalink
https://hdl.handle.net/2142/20875
Description
Title
Altered estrogen receptor and transforming growth factor pathways in models of estrogen-autonomous and of antiestrogen-resistant MCF-7 human breast cancer cells
Author(s)
Herman, Mary E.
Issue Date
1995
Doctoral Committee Chair(s)
Katzenellenbogen, Benita S.
Department of Study
Molecular and Integrative Physiology
Discipline
Physiology
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Cell
Biology, Animal Physiology
Language
eng
Abstract
The progression of breast tumors to steroid-autonomous and antiestrogen-resistant phenotypes confounds our ability to treat breast cancer with antiestrogens, the most efficacious hormone treatment used clinically. We developed two models in the MCF-7 cell line, an estrogen receptor-positive human breast cancer cell line, to assess the relative importance of the estrogen receptor pathway and the transforming growth factor (TGF) pathways during this progression. MCF-7 cells maintained long-term in steroid-deprived conditions exhibited a decreased growth reliance on estrogen despite elevated levels of estrogen receptor. Antiestrogen sensitivity was maintained and estrogen receptor function appeared normal. Expression of TGF$\alpha$ and the TGF-$\beta$s was transiently altered in response to steroid-deprivation; basal expression was partially reestablished in the long-term steroid-deprived sublines. We observed decreased growth responsiveness to TGF$\alpha$ and the TGF-$\beta$s, suggesting that these autocrine factors were not primary growth regulators of the steroid-autonomous MCF-7 sublines. Our second model involved long-term exposure of MCF-7 cells to the antiestrogen, trans-OH-tamoxifen (TOT). The resulting phenotype showed a growth-stimulation, rather than growth-inhibition in response to TOT and deregulation of progesterone receptor expression. Several other parameters of estrogen receptor structure and function, including responsiveness to pure antiestrogens, were analyzed and appeared normal, despite a 40% reduction in estrogen receptor content. This subline exhibited decreased growth-inhibition in response to retinoic acid and a complete loss of growth suppression by TGF-$\beta$1. Insensitivity to TGF-$\beta$1 could not be accounted for by loss of TGF-$\beta$ receptor or cell signalling. Growth-stimulation by TOT was partly, and insensitivity to TGF-$\beta$ fully, reversible upon maintenance in TOT-deprived culture conditions. Interestingly, this subline expressed elevated levels of TGF-$\beta$ mRNAs and secreted, bioactive protein. The altered growth responsiveness of this model should prove useful in understanding antiestrogen resistance. Furthermore, it may provide insight into the potential role(s) of the TGF-$\beta$s in tumor progression.
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