Estrogen-related receptor tied to tamoxifen resistance in lobular breast cancer

NEW YORK (Reuters Health) - Using a novel model of invasive lobular breast cancer, US researchers have found that increased expression of estrogen-related receptor (ERR) gamma is associated with resistance to tamoxifen.

"Until now, this receptor has not been viewed to be of much importance in any type of breast cancer," lead author Dr. Rebecca Riggins, from Georgetown University Medical Center in Washington, DC, said in a statement. "All that was known is that there were more of these receptors in breast cancer than in normal breast tissue."

According to the report, which appears in the November 1st issue of Cancer Research, most studies examining endocrine resistance have focused on invasive ductal carcinoma. Although that type of breast cancer is the most common, invasive lobular carcinoma still accounts for up to 15% of new cases. Moreover, while rates of ductal disease have remained fairly stable for the last 20 years, rates of lobular disease continue to climb.

In their paper, the research team describes the creation of the first cell culture model of tamoxifen-resistant, invasive lobular breast carcinoma. The cell line they developed showed decreased expression of estrogen receptor alpha and increased expression of ERR-gamma.

Knocking out the ERR-gamma overexpression rendered the cells sensitive to tamoxifen. Conversely, forcing ERR-gamma overexpression in standard lobular breast cancer cells made them resistant to tamoxifen.

Further analyses showed that ERR-gamma-driven transcription was increased in the tamoxifen-resistant cells, but that inhibition of activator protein 1 (AP1) can enhance or even restore tamoxifen sensitivity.

These results, the authors conclude, "support a role for ERR-gamma/AP1 signaling in the development of tamoxifen resistance, and suggest that expression of ERR-gamma may be a marker of poor tamoxifen response."

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