Stress in Metastatic Breast Cancer: To the Bone and Beyond

Abstract

Breast cancer (BRCA) remains as one the most prevalent cancers diagnosed in industrialised countries. Although the overall survival rate is high, the dissemination of BRCA cells to distant organs correlates with a significantly poor prognosis. This is due to the fact that there are no efficient therapeutic strategies designed to overcome the progression of the metastasis. Over the past decade, critical associations between stress and the prevalence of BRCA metastases were uncovered. Chronic stress and the concomitant sympathetic hyperactivation have been shown to accelerate the progression of the disease and the metastases incidence, specifically to the bone. In this review, we provide a summary of the sympathetic profile on BRCA. Additionally, the current knowledge regarding the sympathetic hyperactivity, and the underlying adrenergic signalling pathways, involved on the development of BRCA metastasis to distant organs (i.e., bone, lung, liver and brain) will be revealed. Since bone is a preferential target site for BRCA metastases, greater emphasis will be given to the contribution of α2- and β-adrenergic signalling in BRCA bone tropism and the occurrence of osteolytic lesions.

Profiling the Adrenergic System in Breast Cancer and the Development of Metastasis

“…BC subtypes (luminal A, luminal B, HER2-enriched, and basal-like) display different prognosis and disease outcomes [ 45 ], with the luminal subtype presenting more propensity to metastasize to the bone [ 43 ]. Since 95% of BC patients expressing higher levels of catecholamines are of the luminal subtype, we further characterized the expression profile of each BC subtype.…”

“…Hence, in accordance with the sample collection site, BC cell lines can be classified as primary (collected within breast tissue) or metastasis (collected outside the breast, e.g., skin, pleural effusion, ascites, lymph nodes, pericardial effusion, central nervous system). In line with the scope of this study and given the relevance of the sympathetic signature in BC and the establishment of metastasis [ 45 ], we further pursued studies evaluating whether the sympathetic marker genes were differentially expressed between the primary (n = 24) versus metastatic BC cell lines (n = 28; Figure 6 c,d). As shown in Figure 6 c, most primary BC cell lines represent the basal-like subtype, while the metastatic BC cell lines were distributed along the four different subtypes (luminal A, luminal B, HER2-enriched, and basal-like).…”

“…For this matter, MCF-7 and MDA-MB-231 are the cell lines mostly employed [ 24 , 68 ]. Nonetheless, as discussed elsewhere [ 45 ], the results obtained in previous work regarding the physiological role of stress in BC development are often contradictory and sometimes difficult to replicate, in particular, the use of β-blockers in BC patients. Our comprehensive analysis on the adrenergic profile of human BC cell lines using the CCLE database showed for the first time that the genes of ADRs, catecholamine metabolic enzymes, and transporters were differently expressed depending on the BC cell line and BC subtype, and thus might justify this problem.…”

The Role of Telomerase in Breast Cancer’s Response to Therapy

“…Breast cancer cells acquire a very dynamic characteristic that is associated with tumor cells’ ability to induce the epithelial–mesenchymal transition (EMT) and, conversely, the mesenchymal–epithelial transition (MET) [ 7 ]. Consequently, by changing their phenotype, cells are able to escape the bulk, enter the cardiovascular system, and metastasize to lymph nodes and distant organs such as bones, the liver, or the brain [ 7 , 8 ]. The ability of breast cancer cells to metastasize is the main cause for treatment failure and patient deaths.…”

Bifunctional scaffolds for tumor therapy and bone regeneration: Synergistic effect and interplay between therapeutic agents and scaffold materials

“…Osteosarcoma often occurs in children and adolescents as a primary malignant bone tumor [ 4 ]. However, most tumors tend to metastasize to the bone, among which prostate cancer [ 5 ] and breast cancer [ 6 ] all have a high chance of bone metastasis. The clinical treatment of bone tumors is generally based on surgery supplemented by radiotherapy and/or chemotherapy [ 7 , 8 ].…”