Temporal and spatial changes in bone mineral content and mechanical properties during breast-cancer bone metastases.

Cancer cells favour migration and metastasis to bone tissue for 70-80 % of advanced breast cancer patients and it has been proposed that bone tissue provides attractive physical properties that facilitate tumour invasion, resulting in osteolytic and or osteoblastic metastasis. However, it is not yet known how specific bone tissue composition is associated with tumour invasion. In particular, how compositional and nano-mechanical properties of bone tissue evolve during metastasis, and where in the bone they arise, may affect the overall aggressiveness of tumour invasion, but this is not well understood. The objective of this study is to develop an advanced understanding of temporal and spatial changes in nano-mechanical properties and composition of bone tissue during metastasis. Primary mammary tumours were induced by inoculation of immune-competent BALB/c mice with 4T1 breast cancer cells in the mammary fat pad local to the right femur. Microcomputed tomography and nanoindentation were conducted to quantify cortical and trabecular bone matrix mineralisation and nano-mechanical properties. Analysis was performed in proximal and distal femur regions (spatial analysis) of tumour-adjacent (ipsilateral) and contralateral femurs after 3 weeks and 6 weeks of tumour and metastasis development (temporal analysis). By 3 weeks post-inoculation there was no significant difference in bone volume fraction or nano-mechanical properties of bone tissue between the metastatic femora and healthy controls. However, early osteolysis was indicated by trabecular thinning in the distal and proximal trabecular compartment of tumour-bearing femora. Moreover, cortical thickness was significantly increased in the distal region, and the mean mineral density was significantly higher in cortical and trabecular bone tissue in both proximal and distal regions, of ipsilateral (tumour-bearing) femurs compared to healthy controls. By 6 weeks post-inoculation, overt osteolytic lesions were identified in all ipsilateral metastatic femora, but also in two of four contralateral femora of tumour-bearing mice. Bone volume fraction, cortical area, cortical and trabecular thickness were all significantly decreased in metastatic femora (both ipsilateral and contralateral). Trabecular bone tissue stiffness in the proximal femur decreased in the ipsilateral femurs compared to contralateral and control sites. Temporal and spatial analysis of bone nano-mechanical properties and mineralisation during breast cancer invasion reveals changes in bone tissue composition prior to and following overt metastatic osteolysis, local and distant from the primary tumour site. These changes may alter the mechanical environment of both the bone and tumour cells, and thereby play a role in perpetuating the cancer vicious cycle during breast cancer metastasis to bone tissue.

Emerging Evidence of the Functional Impact of the miR379/miR656 Cluster (C14MC) in Breast Cancer.

Many microRNAs exist in clusters that share comparable sequence homology and may target genes in a common pathway. The miR-379/miR-656 (C14MC) cluster is imprinted in the DLK1-Dio3 region of 14q32.3 and contains 42 miRNAs. It plays a functional role in numerous biological pathways including vascular remodeling and early development. With many C14MC miRNAs highlighted as potential tumor suppressors in a variety of cancers, the role of this cluster in breast cancer (BC) has garnered increased attention in recent years. This review focuses on C14MC in BC, providing an overview of the constituent miRNAs and addressing each in terms of functional impact, potential target genes/pathways, and, where relevant, biomarker capacity. Studies have revealed the regulation of key factors in disease progression and metastasis including tyrosine kinase pathways and factors critical to epithelial-mesenchymal transition (EMT). This has potentially important clinical implications, with EMT playing a critical role in BC metastasis and tyrosine kinase inhibitors (TKIs) in widespread use for the treatment of BC. While the majority of studies have reported tumor-suppressing roles for these miRNAs, some have highlighted their potential as oncomiRs. Understanding the collective contribution of miRNAs within C14MC to BC may support improved understanding of disease etiology and present novel approaches to targeted therapy.

Boron clusters as breast cancer therapeutics.

Since the foundation of small molecule-based therapeutics over 100 years ago, their design has been dominated by organic based components. This has also been apparent in anti-cancer therapeutics in a broad range of strategies; from the older DNA chelating drugs, to the more recent molecular-targeted therapies. The main challenges facing current treatments; multidrug resistance and low therapeutic index, can potentially be alleviated by the incorporation of boron clusters. While retaining the versatility of their organic counterparts, these compounds offer a unique set of molecular interactions, which are a useful tool in targeted therapies and can improve many organic formulations with their incorporation. This review will discuss the potential of boron clusters in medicine while focusing on their activity in the breast cancer setting.