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Loss of TGF-beta signaling in breast cancer impairs response
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Below-normal amounts of the protein TGFBR2 may be predictive of breast cancer resistance to the anti-estrogen drug tamoxifen, according to study results.
Estrogen is a hormone that forces cells to grow and divide while the transforming growth factor (TGF)-beta cell signaling pathway exerts effects of growth-inhibition, according to study background. Both estrogen and TGF-beta signaling pathways interact — directly and indirectly — and if there is an abnormality with one pathway, it can possibly interfere with the activation of the other.
Susann Busch, PhD, of the Sahlgrenska Cancer Center at Gothenburg University in Sweden, and colleagues conducted the study to demonstrate that the loss of TGFBR2 expression is predictive of a resistance to tamoxifen in ER-positive breast cancer.
The researchers analyzed tumor samples from 564 premenopausal women enrolled in a clinical trial between 1986 and 1991. After surgery, the patients were randomly assigned tamoxifen for 2 years (n = 276) or to not have a systemic treatment (n = 288).
Among the women who received tamoxifen and who had ER-positive tumors, those with tumors with low levels of the TGFBR2 protein had an approximately 73% (HR = 0.267; 95% CI, 0.098-0.731) lower RFS rate vs. tumors that had high levels of TGFBR2.
Additionally, there was an association between low TGFBR2 with RFS after an analysis of data from four independent gene expression data sets of tamoxifen-treated breast cancer (P < .05).
The researchers then evaluated breast cancer cell lines to determine how TGF-beta signaling influences tamoxifen treatment outcomes. The absence of TGFBR2 changed the cells so they would not respond to estrogen and tamoxifen. In those drug-resistant cell lines, the researchers identified low levels of TGFBR2 and abnormal pathway activation, which confirmed its relevance in drug resistance development.
“Our studies established the role of the cell signaling protein TGFBR2 in hormone therapy resistance in breast cancer,” Busch said in a press release. “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.” – by Anthony SanFilippo
Disclosure: The researchers report no relevant financial disclosures.
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