Identifying new approaches to the treatment of endocrine resistant breast cancer

乳腺癌是影响女性的最常见癌症。高达80%的乳腺癌患者的肿瘤细胞含有一种蛋白质，称为雌激素受体α（ER）。ER介导激素雌激素的作用，并有助于乳腺癌细胞的生长和增殖。当癌症只影响乳房时，通常是容易治疗的。不幸的是，当乳腺癌细胞扩散（转移）到身体的其他部位时，这种疾病就变得无法治愈。目前，大多数含有雌激素受体的肿瘤都是通过激素治疗来降低体内雌激素的水平，从而阻断雌激素受体的作用。这通常在最初成功地控制癌症，但在癌症已经扩散的情况下，最终药物停止有效;耐药性发展。目前，当这种情况发生时，患者几乎没有其他治疗选择-通常使用不同类型的激素治疗。这也可能是有效的最初，但随着每一个新的抗激素药物的使用，疗效的持续时间变得越来越短。已经提出了对这些激素治疗产生抗性的许多机制。在过去的18个月里，重要的新研究发现，在大约40%的乳腺癌患者中，ER基因存在突变，并且据信这些突变克服了ER被雌激素激活的需要，因此尽管雌激素减少治疗，这些癌症仍在生长。迫切需要在实验室中确定这些突变ER蛋白的作用机制，以便为ER突变患者确定治疗方案。为了做到这一点，该实验室已经创建了转移性乳腺癌细胞，这些细胞已经被遗传修饰以获得ER突变。这些细胞重现了对激素治疗的抗性，因此代表了确定突变蛋白如何工作以及快速评估新治疗以克服激素治疗抗性的非常有用的手段。在雌激素存在的情况下，ER还可以与调节其他基因表达的特定蛋白质（转录因子）结合。这些其他基因中的一些调节负责检测激素、胆汁酸和其他物质（核受体）的蛋白质，而其他基因对许多细胞功能（包括代谢和信号传导（激酶））至关重要。我们已经发现，这些蛋白质中的一些蛋白质的水平在ER突变的乳腺癌细胞中增加。我们建议，针对这些蛋白质中的一个或多个的药物可以提供治疗ER突变的乳腺癌的方法。我们的目标是进行研究与细胞系的突变ER蛋白，以确定是否有任何的过度代表的蛋白质是重要的这些癌细胞的生长和测试，如果阻断他们的行动与特定的药物可以用来杀死细胞与ER突变。靶向许多这些上调蛋白质的药物已经可用并用于其他临床环境，因此如果发现有效，可以很容易地重新利用。如果我们的研究结果表明这些药物对乳腺癌细胞有效，我们将在未来开展临床试验，以证实这些发现在乳腺癌患者中的作用。这项工作将由医学肿瘤学专家注册官Kirsty Balachandran博士进行，他致力于通过研究实验室中潜在的新治疗策略来改善乳腺癌患者的护理，并开发这些策略以扩大临床实践中可用的疗法。

Breast cancer is the most common cancer that affects women. Up to 80% of patients with breast cancer have tumour cells that contain a protein, known as the estrogen receptor alpha (ER). ER mediates the effects of the hormone, estrogen and is instrumental to the growth and proliferation of breast cancer cells. When cancer affects the breast alone, it is often readily treatable. Unfortunately, when breast cancer cells spread (metastasise) to other parts of the body, the disease becomes incurable. It is believed that higher levels of ER in certain breast cancers may contribute to the risk of spread and the cancer consequently becoming incurable.Currently, most tumours that contain ER are treated with hormone treatments that reduce the levels of estrogen in the body and thereby block the actions of ER. This is often initially successful at controlling the cancer but in the case of cancer that has spread, eventually the drug stops being effective; resistance develops. At present, there are very few other treatment options available for patients when this happens - usually a different type of hormone treatment is used. This may also be effective initially but with each new anti-hormone drug used, the duration of efficacy becomes shorter and shorter. Many mechanisms for the development of resistance to these hormone treatments have been proposed. In the last 18 months, important new studies have discovered that in about 40% of patients who have breast cancer that has spread and become resistant to hormone treatment, mutations in the ER gene are present and it is believed that these mutations overcome the need of ER to be activated by estrogen and thus these cancers grow despite the estrogen reducing therapies. There is an urgent need to determine the mechanisms of action of these mutant ER proteins in the laboratory, so as to identify treatment options for patients with ER mutations. To do this, the laboratory has created metastatic breast cancer cells that have been genetically modified to gain the ER mutations. These cells recapitulate resistance to hormone treatments and so represent a very useful means of determining how the mutant proteins work and for rapid evaluation of new treatments to overcome hormone treatment resistance. In the presence of estrogen, ER can also bind with specific proteins (transcription factors) that regulate the expression of other genes. Some of these other genes regulate proteins that are responsible for the detection of hormones, bile acids and other substances (nuclear receptors) whilst others are essential to many cellular functions including metabolism and signalling (kinases). We have found that levels of some of these proteins are increased in the breast cancer cells with ER mutations. We propose that drugs that target one or more of these proteins could provide the means to treat breast cancer with ER mutations.We aim to carry out studies with the cell lines making the mutant ER proteins, to determine if any of the over-represented proteins are important for growth of these cancer cells and to test if blocking their action with specific drugs can be used to kill cells with ER mutations. Drugs that target many of these up-regulated proteins are already available and used in other clinical settings so may easily be repurposed if found to be effective. If our findings suggest that these drugs are efficacious in breast cancer cells, we would develop a clinical trial in the future to confirm these findings in patients with breast cancer. The work will be conducted by Dr Kirsty Balachandran, a specialist registrar in medical oncology who is dedicated to improving the care patients with breast cancer receive by investigating potential new treatment strategies in the laboratory and developing these to expand therapies available in clinical practice.