Sep 16 : A team of scientists have identified a gene that plays a linchpin role in the ability of breast cancer cells to respond to oestrogen.

The University of Iowa researchers have said that the finding could lead to improved therapies for hormone-responsive breast cancers and might explain differences in the effectiveness of current treatments.

Oestrogen causes hormone-responsive breast cancer cells to grow and divide by interacting with oestrogen receptors made by cancer cells. Interfering with oestrogen signalling is the basis of two common breast cancer therapies - tamoxifen, which blocks oestrogen’s interaction with a primary oestrogen receptor called ER-alpha, and aromatase inhibitors that reduce the amount of oestrogen the body makes and therefore affect any pathway that uses oestrogen.

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, found a central role for transcription factor AP2C (TFAP2C) in controlling multiple pathways of oestrogen signalling.

“Oestrogen binds to oestrogen receptors and triggers a cascade of events including gene regulation. We found that elimination of the TFAP2C from the cell causes all of those cascades that we associate with oestrogen to go away. The treated cancer cells were not able to respond to estrogen by any normal pathway,” said Prof. Weigel.

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 oestrogen receptor called GPR30 that is found at the cancer cell membrane. The team also showed that these effects inhibited tumour growth. Specifically, the treated cancer cells did not grow in response to oestrogen and establishment of tumours in mice was delayed.

Prof. Weigel said the finding further suggested that there were many pathways that allowed cells to respond to oestrogen, and that TFAP2C was 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,” Prof. Weigel said.

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

Prof. Weigel noted that advancing understanding of oestrogen regulation and hormone-response in breast cancer was 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. 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,” Prof. Weigel said.

The study is published in the Sept. 15 issue of Cancer Research. (ANI)