Tamoxifen Resistance Predicted by Molecular Marker

Below normal levels of the protein TGF-beta receptor type 2 (TGFBR2) in breast tumors, correlated with resistance of these tumors to tamoxifen, an antiestrogen therapy for estrogen receptor (ER)-positive breast cancer.

Women with ER-positive breast cancer who received tamoxifen and whose tumors expressed low levels of TGFBR2, and also had low TGFBR2 messenger RNA levels, had a 73% lower recurrence-free survival rate compared with patients whose tumors expressed relatively high levels of the protein.

These results are published in the April 1, 2015 issue of Cancer Research.  

Low TGFBR2 protein levels in breast tumors were also associated with worse recurrence-free survival when the data was analyzed from four independent and publically available gene expression data sets of women with breast cancer who were treated with tamoxifen.

Susann Busch, PhD, a postdoctoral fellow and Göran Landberg, MD, PhD, professor, of the Sahlgrenska Cancer Center in Gothenburg University, Sweden, and colleagues analyzed tumor samples from 564 premenopausal patients who were enrolled in a clinical trial between 1986 and 1991. All patients had surgery and radiotherapy, and were then randomized one to one to either tamoxifen for 2 years or no adjuvant treatment.

About one-third of women with ER-positive breast cancer treated with tamoxifen either do not respond to initial tamoxifen therapy or develop resistance.

Prior studies have demonstrated that both estrogen and TGF-beta signaling pathways can directly and indirectly interact with each other, and that abnormal regulation of either pathway may interfere with activation of the other pathway. High TGFBR2 expression has also been shown to be a poor prognostic indicator of overall survival in women with ER-negative disease.

Busch and colleagues therefore hypothesized that those women who are not responsive to tamoxifen may have tumors with aberrant TGF-beta signaling.

In addition to studying tumor samples, using breast cancer cell lines, the authors found that without TGFBR2 expression, these cell lines do not respond to estrogen or tamoxifen treatment. Additionally, a tamoxifen-resistant breast cancer cell line had low TGFBR2 expression and abnormal TGF-beta pathway activation, suggesting the potential importance of this pathway in the resistance to tamoxifen. Tamoxifen typically induces apoptosis of sensitive cell lines, but in those cells with decreased TGFBR2 expression, apoptosis was impaired upon tamoxifen exposure.

"Our studies established the role of the cell signaling protein TGFBR2 in hormone therapy resistance in breast cancer," said Busch in a statement. "Our data indicate that TGFBR2, which detects TGF-beta and thereby activates subsequent cellular responses, could be used as a marker in the clinics to identify patient subgroups that may not benefit from hormone therapy alone and may require additional therapies."