Inhibition of breast cancer metastasis through targeting of laminin-10 function

在澳大利亚，每11名女性中就有一人罹患乳腺癌。虽然乳腺癌在早期被发现时是高度可治愈的，但当疾病扩散到骨骼和肺等其他器官时，目前的治疗方法是无效的。因此，迫切需要治疗晚期疾病的新疗法。我们发现，层粘连蛋白-10是一种存在于乳房中的蛋白质，被认为控制着乳房的正常发育和成熟，在侵袭性肿瘤以及那些扩散到骨骼和肺部的肿瘤中尤其丰富，这表明这种蛋白质可能在乳腺癌细胞向其他器官扩散的过程中发挥了作用。与此一致，我们发现层粘连蛋白-10在培养中刺激乳腺肿瘤细胞的黏附和移动，这两种活动是肿瘤细胞成功转移所必需的。这些项目的总体目标是证明通过干扰层粘连蛋白-10的功能可以抑制乳腺癌的转移。为此，我们将测量阻断乳腺肿瘤细胞中LN-10的产生对其转移能力的影响。或者，我们将测试层粘连蛋白-10片段的能力，以阻止层粘连蛋白-10诱导的肿瘤细胞的生长和移动(它们从乳房逃脱所需)和活性(它们在远处器官中建立所必需的)。我们将产生针对最具抑制作用的片段的抗体，并在临床相关的乳腺癌转移小鼠模型中测试它们对自发转移的影响，试图阻止-逆转疾病的发展。如果成功，该项目将为开发靶向层粘连蛋白-10的新型抑制剂治疗晚期乳腺癌奠定基础。

Breast cancer affects 1 in 11 women in Australia. Whilst breast cancer is highly curable when detected early, current treatments are ineffective when the disease has spread to other organs such as bone and lungs. Thus, novel therapies for the treatment of advance disease are urgently needed. We have found that laminin-10, a protein present in the breast and thought to control normal breast development and maturation, is particularly abundant in aggressive tumours as well as in those that have spread to bone and lungs suggesting that this protein may play a role in the dissemination of breast cancer cells to other organs. Consistent with this, we have found that laminin-10 stimulates breast tumour cell adhesion and movement in culture, two activities required for successful metastasis of tumour cells. The overall objective of the projects is to demonstrate that breast cancer metastasis can be inhibited by interefering with the function of laminin-10. To this end, we will measure the effect of blocking the production of LN-10 in breast tumour cells on their ability to metastasise. Alternatively, we will test fragments of laminin-10 for their ability to block laminin-10-induced tumour cell growth and movement (required for their escape from the breast) and viability (required for their establishment in distant organs). We will generate antibodies against the most inhibitory fragments and test their effect on spontaneous metastasis in a clinically relevant mouse model of breast cancer metastasis in an attempt to stop-reverse the progression of the disease. If successful, this project will provide the foundation for the development novel inhibitors targeting laminin-10 for the treatment of patients with advanced breast cancer.