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Production of and responsiveness to transforming growth factor-beta in normal and oncogene-transformed human mammary
E M Valverius1, D Walker-Jones, S E Bates
1Vincent Lombardi Cancer Research Center, Georgetown University Hospital, Washington DC 20007.
Abstract:
Transforming growth factors-beta (TGF beta) are a family of closely related, ubiquitously expressed growth factors with the common properties of induction of growth inhibition and expression of differentiation-related markers in epithelial cells. We investigated the role of TGF beta 1 in growth regulation of normal human mammary epithelial cells and in benzo(a)pyrene immortalized sublines further transformed by oncogenes in retroviral vectors. The normal cells were markedly growth inhibited by TGF beta 1, produced TGF beta in a latent form, and expressed TGF beta receptors. In the immortalized cells, both TGF beta-induced growth inhibition and TGF beta receptor binding were reduced. With the single oncogenes v-Ha-ras, v-mos, and SV40 T, growth sensitivity to TGF beta 1 increased, but TGF beta production or TGF beta receptor expression was not altered. Transformation to full malignancy by both SV40 T and v-Ha-ras led to escape from growth inhibition by TGF beta under anchorage-independent, but not anchorage-dependent, conditions without affecting TGF beta production or receptor characteristics. Thus, modulation of TGF beta growth responsiveness in these normal and oncogene transformed human mammary epithelial cells apparently occurs at a level distal to TGF beta receptor binding and is not solely correlated to expression of transforming oncogenes. Further, modulation of TGF beta production is not an indicator of malignant transformation in this system.
Insights
Transforming growth factor-beta 1 (TGF beta 1) inhibits normal mammary cell growth but loses this effect in immortalized and malignant cells. This loss of sensitivity occurs downstream of TGF beta receptor binding.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Transforming growth factors-beta (TGF beta) are crucial regulators of epithelial cell growth and differentiation.
- Understanding TGF beta 1's role in mammary epithelial cells is key to deciphering cancer development.
Purpose of the Study:
- To investigate the role of TGF beta 1 in the growth regulation of normal human mammary epithelial cells.
- To examine how oncogene transformation affects TGF beta 1 sensitivity and signaling in these cells.
Main Methods:
- Utilized normal human mammary epithelial cells and sublines immortalized and transformed by oncogenes (v-Ha-ras, v-mos, SV40 T).
- Assessed TGF beta 1-induced growth inhibition, TGF beta production, and TGF beta receptor binding.
- Evaluated cellular responses under anchorage-dependent and -independent conditions.
Main Results:
- Normal cells showed marked growth inhibition by TGF beta 1, with latent TGF beta production and receptor expression.
- Immortalized cells exhibited reduced TGF beta 1-induced growth inhibition and receptor binding.
- Single oncogene expression increased growth sensitivity to TGF beta 1, without altering TGF beta production or receptor characteristics.
- Malignant transformation led to escape from TGF beta 1 inhibition under anchorage-independent conditions.
Conclusions:
- Modulation of TGF beta 1 growth responsiveness occurs distal to receptor binding in transformed mammary epithelial cells.
- Loss of TGF beta 1 sensitivity is not solely correlated with oncogene expression.
- Altered TGF beta production is not a reliable indicator of malignant transformation in this model system.