Linchpin Gene May Be Useful Target For Breast Cancer Therapies

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University of Iowa researchers have discovered a gene that plays a linchpin 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 causes hormone-responsive breast cancer cells to grow and divide by interacting with estrogen receptors made by cancer cells. Interfering with estrogen signaling is the basis of two common breast cancer therapies—tamoxifen, which blocks estrogen’s interaction with a primary estrogen receptor called ER-alpha, and aromatase inhibitors that reduce the amount of estrogen the body makes and therefore affect any pathway that uses estrogen.

The study, led by Ronald Weigel, M.D., Ph.D., professor and head of surgery at the University of Iowa Roy J. and Lucille A. Carver College of Medicine, reveals a central role for transcription factor AP2C (TFAP2C) in controlling multiple pathways of estrogen signaling. The findings are published in the Sept. 15 issue of Cancer Research.

“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 ER-alpha made by the cancer cell. This reduction in ER-alpha (down to 16 percent of the level normally made by breast cancer cells) also affected production of other “downstream” genes involved in cancer growth.

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

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

The finding suggests that there are many pathways that 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.

Weigel noted that advancing understanding of estrogen regulation and hormone-response in breast cancer is just one part of a larger focus on breast health at the UI.

“The UI has a great interest in breast cancer. Within the next couple of months, the UI Breast Health Clinic will be open and part of its mission is advancing both basic and clinical research in breast cancer,” he said. “This study is one example of how we are moving forward in unlocking the mysteries behind what controls the ability of a breast cancer to respond to estrogen.”

The study is funded in part by the National Institutes of Health and by the Kristen Olewine Milke Breast Cancer Research Fund.

In addition to Weigel, the research team included George Woodfield, a UI research assistant; Yizhen Chen, Ph.D., a UI postdoctoral research fellow in surgery; and Annamarie Horan, Ph.D., in the Department of Surgery at University of Pennsylvania, Philadelphia.

Source: University of Iowa Health Sciences

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