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Resistance to transforming growth factor beta and activin due to reduced receptor expression in human breast tumor
E Kalkhoven1, B A Roelen, J P de Winter
1Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht, The Netherlands.
Abstract:
Loss of sensitivity to growth inhibition by transforming growth factor (TGF)-beta is a phenomenon often observed in human epithelial tumor cells and is linked to malignant progression. We tested a panel of estrogen receptor (ER)-positive and -negative breast cell lines for their sensitivity to TGF-beta and a related member of the TGF-beta superfamily, activin. Both TGF-beta-sensitive (MCF7, Hs578T, and BT20) and -resistant (two T47D variants, ZR75-1, MDA-MB231, and MDA-MB468) cell lines were found, with no strict correlation between ER content and sensitivity to TGF-beta. In contrast, all four ER-positive cell lines were inhibited by activin A, whereas the ER-negative lines were not. To examine whether resistance to TGF-beta and activin resulted from the absence of the corresponding receptors, mRNA expression of the types I and II receptors was studied. TGF-beta receptor II was not expressed in the two T47D variants and was low in ZR75-1 cells. Upon stable transfection of the TGF-beta receptor II in one of the T47D variants, sensitivity to TGF-beta 1 and TGF-beta 2 was restored with respect to inhibition of anchorage-dependent and -independent proliferation, indicating that other signal transduction components are functionally intact. Sensitivity to TGF-beta in the transfectants was dependent on the expression level of the newly introduced receptor. Resistance to activin in the ER-negative cell lines could be explained in BT20 and Hs578T cells, but not in MDA-MB231 and MDA-MB468, by low activin receptor expression. These results show that resistance to TGF-beta and activin is often, but not always, due to reduced expression of the signaling receptor in breast cancer cells. The activin resistance of ER-negative breast tumor cells may be involved in their increased malignancy compared with ER-positive cells.
Insights
Loss of sensitivity to transforming growth factor-beta (TGF-β) and activin signaling in breast cancer cells is often due to reduced receptor expression. Restoring TGF-β receptor II expression can re-sensitize cells, suggesting a role in malignancy.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Loss of sensitivity to transforming growth factor-beta (TGF-β) is linked to human epithelial tumor progression.
- Estrogen receptor (ER) status is a key factor in breast cancer classification and treatment.
Purpose of the Study:
- To investigate the sensitivity of ER-positive and ER-negative breast cancer cell lines to TGF-β and activin.
- To determine if reduced receptor expression contributes to resistance against these growth factors.
Main Methods:
- Screening of breast cancer cell lines for TGF-β and activin sensitivity.
- Analysis of mRNA expression for TGF-β and activin receptors.
- Stable transfection of TGF-β receptor II to assess restoration of sensitivity.
Main Results:
- Breast cancer cell lines showed variable sensitivity to TGF-β, with no strict correlation to ER status.
- ER-positive cell lines were inhibited by activin A, while ER-negative lines were resistant.
- Reduced TGF-β receptor II expression was observed in resistant cell lines; re-expression restored TGF-β sensitivity.
- Activin resistance in ER-negative lines was partly explained by low activin receptor expression.
Conclusions:
- Resistance to TGF-β and activin in breast cancer is frequently associated with reduced signaling receptor expression.
- Restoration of TGF-β receptor II can reverse resistance, indicating functional downstream signaling.
- Activin resistance in ER-negative breast tumor cells may contribute to their more aggressive nature.