Linchpin gene may be useful target for new breast cancer therapies

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."

发现关键基因可能成为乳癌治疗新方法

部分乳腺癌细胞的生长是雌激素依赖性的，通过手术切除内分泌腺体或注入外源性激素来调整患者体内的雌激素水平，可以达到抑制肿瘤细胞分离，控制其发展的作用，但由于乳腺纤维囊性增生病的发病机理还未完全阐明，外源性激素的应用很难得到理想的效果。激素在治疗过程中确能暂时减轻症状，但长期使用必将造成体内激素之间新的失衡。

爱荷华大学研究人员已经发现一种基因，在乳腺癌细胞与雌激素反应过程中起关键作用。由此可能产生更好的治疗激素敏感型乳腺癌方法，并可能解释目前治疗效果的差异。
雌性激素与乳腺癌细胞的雌性激素结合受体相结合导致乳腺癌细胞的生长和分化。干扰雌性激素信号是两种常见的乳腺癌疗法的理论基础。它莫西芬能够阻止雌性激素与原发性雌激素受体（ER-alpha）的互作，芳香酶抑制剂能够降低雌性激素的量并因此影响乳腺癌发生过程中对雌性激素的利用。
医学博士Ronald Weigel 教授与爱荷华大学Roy J.和Lucille A.组成的研究小组发现了控制多种雌性激素信号途径的重要转录因子AP2C（TFAP2C）。这些发现刊登在9月15日出版的Cancer Research上。
"雌激素结合雌激素受体结合，并引发包括基因调控在内的一系列反应 "，研究小组成员之一weigel说道 ，"我们发现，抑制癌细胞中的TFAP2C后，与雌性激素相关联的一系列反应都没有了，细胞无法通过任何正常途径与雌性激素发生互作。 "
研究者发现TFAP2C的表达被沉默后，乳腺癌细胞中的ER-alpha数量明显减少。ER-alpha的减少，也影响包含肿瘤生长基因在内的一些下游基因的表达。
此外，在沉默TFAP2C的时候也会敲除癌细胞的细胞膜中存在的一个称为GPR30的雌激素受体。
重要的是，该研究小组通过小鼠试验发现，这些效应抑制肿瘤的生长。即使在雌激素的刺激下，癌细胞也不再生长。研究表明，细胞通过很多途径与雌激素发生互作，而TFAP2C是控制激素互作的一个重要因子。
"针对这个基因来开发药物治疗乳腺癌可能是一个不错的方法，因为它能针对多种不同的途径 " weigel说。
结果也可以解释为什么它莫西芬的疗效芳香酶抑制剂好，因为它只是以单一途径为靶标，而后者却可能影响多种激素通路。
weigel指出，更深入了解雌激素调节与乳腺癌的激素敏感反应只是UI研究中一部分，更多的重心是放在乳房健康上面。
"UI对乳腺癌研究有很大的兴趣。在未来几个月，UI乳房健康诊所（UI Breast Health Clinic）将部分开放，其任务就是是推动乳腺癌的基础和临床研究"，他说。 "这项研究是一个我们更进一步了解控制雌激素与乳腺癌互作的秘密例子”。