Silencing expression of the transcription factor AP2C gene, which regulates multiple estrogen signaling pathways in breast cancers, can make tumors unresponsive to estrogen, according to an article in the September 15 issue of Cancer Research.

The researchers, led by Ronald Weigel, MD, PhD, professor and head of surgery at the University of Iowa Roy J. and Lucille A. Carver College of Medicine at the University of Iowa, believe the gene plays a key role in the ability of breast cancer cells to respond to estrogen. The finding may lead to improved therapies for hormone-responsive breast cancers and may explain differences in the effectiveness of current treatments.

"Estrogen binds to estrogen receptors and triggers a cascade of events including gene regulation," said Weigel, who also is a member of the Holden Comprehensive Cancer Center at the UI. "We found that elimination of the TFAP2C from the cell causes all of those cascades that we associate with estrogen to go away. The treated cancer cells were not able to respond to estrogen by any normal pathway."
The researchers found that silencing expression of TFAP2C in hormone-responsive breast cancer cells significantly decreased the amount of primary estrogen receptor (ER-alpha, the target for tamoxifen) made by the cancer cell. This reduction (down to 16 percent of the level normally made by breast cancer cells) also affected production of other downstream gene products involved in cancer growth.

In addition, silencing TFAP2C knocked out expression of another estrogen receptor, GPR30, that is found at the cancer cell membrane.

Importantly, the effects of silencing inhibited tumor growth. Specifically, treated cancer cells did not grow in response to estrogen and establishment of tumors in mice was delayed.

The finding suggests that many pathways allow cells to respond to estrogen and that TFAP2C is a central player in controlling hormone response.

"Targeting this gene may be a better way to develop drugs to treat hormone-responsive breast cancers because it targets multiple different pathways," Weigel said.

The results also may explain why tamoxifen, which targets a single pathway, is less effective that aromatase inhibitors, which likely affect many estrogen pathways.