Bone morphogenetic proteins, breast cancer, and bone metastases: striking the right balance

Bone morphogenetic proteins (BMPs) belong to the TGF-β super family, and are essential for regulation of foetal development, tissue differentiation and homeostasis, and a multitude of cellular functions. Naturally, this has led to the exploration of aberrance in this highly regulated system as a key factor in tumourigenesis. Originally identified for their role in osteogenesis and bone turnover, attention has been turned to the potential role of BMPs in tumour metastases to, and progression within, the bone niche. This is particularly pertinent to breast cancer, which commonly metastasises to bone, and in which studies have revealed aberrations of both BMP expression and signalling which correlate clinically with breast cancer progression. Ultimately a BMP profile could provide new prognostic disease markers. As the evidence suggests a role for BMPs in regulating breast tumour cellular function, in particular interactions with tumour stroma and the bone metastatic microenvironment, there may be novel therapeutic potential in targeting BMP signalling in breast cancer. This review provides an update on the current knowledge of BMP abnormalities and their implication in the development and progression of breast cancer, particularly in the disease specific bone metastasis

Key factors in breast cancer dissemination and establishment at the bone: past, present and future perspectives

Bone metastases associated with breast cancer remain a clinical challenge due to their associated morbidity, limited therapeutic intervention and lack of prognostic markers. With a continually evolving understanding of bone biology and its dynamic microenvironment, many potential new targets have been proposed. In this chapter, we discuss the roles of well-established bone markers and how their targeting, in addition to tumour-targeted therapies, might help in the prevention and treatment of bone metastases. There are a vast number of bone markers, of which one of the best-known families is the bone morphogenetic proteins (BMPs). This chapter focuses on their role in breast cancer-associated bone metastases, associated signalling pathways and the possibilities for potential therapeutic intervention. In addition, this chapter provides an update on the role receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG) play on breast cancer development and their subsequent influence during the homing and establishment of breast cancer-associated bone metastases. Beyond the well-established bone molecules, this chapter also explores the role of other potential factors such as activated leukocyte cell adhesion molecule (ALCAM) and its potential impact on breast cancer cells’ affinity for the bone environment, which implies that ALCAM could be a promising therapeutic target

Reduced expression of RanBPM Is associated with poorer survival from lung cancer and increased proliferation and invasion of lung cancer cells in vitro

Background/Aim: Ran binding protein microtubule-organizing centre (RanBPM), also known as RanBP9, is a scaffold protein conserved through evolution. We investigated the role of RanBPM in human lung cancer. Materials and Methods: Transcripts of RanBPM were determined in 56 human lung cancers along with paired normal lung tissues using real-time PCR. Association with prognosis was analyzed by online Kaplan–Meier survival analysis. In vitro lung cancer cell functional assays examined the impact of RanBPM-knockdown on cellular growth and invasion. Results: Higher expression of RanBPM was observed in tumor when compared to paired normal lung tissues. Increased RanBPM expression was seen in patients with longer overall and disease-free survival. Knockdown of RanBPM in lung cancer cell lines resulted in increased growth and invasion in vitro. Conclusion: Increased expression of RanBPM associates with postponed disease progression and better prognosis. RanBPM plays an inhibitory role in regulating proliferation and invasion of lung cancer cells

Increased expression of follistatin in breast cancer reduces invasiveness and clinically correlates with better survival

Background/Aim: Activin and its antagonist follistatin (FST) have been implicated in several solid tumours. This study investigated the role of FST in breast cancer. Materials and Methods: FST expression was examined using reverse transcription polymerase chain reaction (RT-PCR), real-time quantitative polymerase chain reaction (qPCR) and immunohistochemistry in a cohort of breast cancer samples. Expression was correlated to pathological and prognostic parameters in our patient cohort. FST was overexpressed in MCF-7 cells and assays for growth and invasion were performed. Results: FST is expressed in breast tissue, in the cytoplasm of mammary epithelial cells. Expression was decreased in breast cancer tissue in comparison to normal mammary tissue. Over-expression of FST in vitro led to significantly increased growth rate and reduced invasion. Higher FST associates with lower-grade tumours and better survival. Conclusion: Our results suggest a role for FST as a suppressor of invasion and metastasis in breast cancer

The effects of anesthetics on recurrence and metastasis of cancer, and clinical implications

Surgical resection of the primary tumor may enhance the metastasis and recurrence of cancer. The reaction of patients to surgery includes changes of the immune system, the inflammatory system and the neuroendocrine system. In the perioperative period, anesthetics are used both for anesthesia and analgesia. There are several studies showing that the progression of cancer can be influenced by many kinds of anesthetics, although most of these studies are preclinical and thus have not yet influenced clinical recommendations. This review summarizes recent studies regarding the effects of anesthetics on metastasis and recurrence of cancer

The downstream of tyrosine kinase 7 is reduced in lung cancer and is associated with poor survival of patients with lung cancer

The downstream of tyrosine kinase 7 (DOK7) is an adaptor protein mediating signalling transduction between receptors and intracellular downstream molecules. Reduced expression of DOK7 has been observed in breast cancer. The present study aimed to investigate the role played by DOK7 in lung cancer. The expression of DOK7 at both mRNA and protein levels was evaluated in human lung cancer. A reduced expression of DOK7 transcripts was seen in lung cancers compared with normal lung tissues. Kaplan-Meier analyses showed that the reduced expression of DOK7 was associated with poorer overall survival and progression-free survival of patients with lung cancer. A further western blot analysis revealed a predominant expression of DOK7 isoform 1 (DOK7V1) in normal lung tissues, which was reduced in lung cancer. Forced overexpression of DOK7V1 in lung cancer cell lines, A549 and H3122 resulted in a decrease of in vitro cell proliferation and migration, while adhesion to extracellular matrix was enhanced following the expression. In conclusion, DOK7 was reduced in lung cancer and reduced DOK7 expression was associated with poorer survival. DOK7 isoform 1 plays an inhibitory role on the proliferation and migration of lung cancer cells in which Akt pathway may be involved

Noggin is associated with a poor prognosis of gastric cancer by promoting the proliferation of gastric cancer cells via the upregulation of EGFR

Noggin is an antagonist of bone morphogenetic proteins (BMP), being indispensable for certain developmental events. The present study aimed to examine the role of Noggin in the development and prognosis of gastric cancer (GC) and to elucidate the underlying mechanisms. The expression of Noggin in GC was evaluated by RT‑qPCR, immunohistochemistry and by the analyses of publicly available databases. The effects of Noggin on proliferation, cell cycle, adhesion, invasion, colony formation and tumour spheroid were examined following both the knockdown and overexpression of Noggin in GC cell lines. The involvement of epidermal growth factor receptor (EGFR) signalling was examined by western blot analysis and by using small molecule inhibitors. As a result, a higher expression of Noggin in GC was found to be associated with a poorer overall survival. Noggin overexpression promoted the proliferation and colony formation of GC cells by promoting cell cycle progression. The knockdown of Noggin in HGC27 cells exerted an opposite effect on proliferation, colony formation and cell cycle progression. Noggin expression positively correlated with EGFR expression in both GC cell line models and The Cancer Genome Atlas human GC cohort. Targeting EGFR and its downstream pathways diminished cell proliferation which was promoted by Noggin. Furthermore, Noggin overexpression resulted in an enhanced nuclear translocation of β‑catenin, leading to an upregulation of EGFR. Thus, the findings of the present study demonstrate that Noggin promotes the proliferation of GC cells by upregulating EGFR and enhancing a vicious circle formed by β‑catenin, EGFR, ERK and Akt

The role of Gremlin1 in breast cancer disease progression: relevant molecular and cellular mechanisms

Bone Morphogenetic Proteins (BMPs) are members of the Transforming Growth Factor Beta (TGFβ) family, that were discovered for their role in bone development, but have since been found to regulate cellular differentiation and tissue homeostasis. The cellular effect of BMPs is highly regulated, involving secreted antagonist proteins that directly bind BMPs, dampening BMP signalling. BMPs and their antagonists are of interest for their role in tumourigenesis and metastasis in cancer. Due to their significance in bone homeostasis, they are of particular interest in breast cancer, which commonly metastasises to bone. Despite progress in treatment and outcomes, those with metastatic breast cancer have poor survival. A better understanding of breast cancer biology, and development of prognostic markers and therapeutic targets is required for improved patient outcomes. The Gremlin1 ligands BMP-2, -4 and -7, have been implicated in breast cancer disease progression, but little is known regarding the role of Gremlin1 itself. This work determined that Gremlin1 expression in breast cancer is upregulated, but that its impact is dependent on the subtype and receptor profile of the breast cancer. There is a strong correlation between Gremlin1 and the Human Epidermal Growth Factor Receptor 2 (HER2), wherein upregulated Gremlin1 is a negative prognostic marker. Upregulation of Gremlin1 in HER2+ breast cancer cells increased proliferation, migration, and markers of epithelial to mesenchymal transition (EMT). In vivo Gremlin1 promoted HER2+ tumour growth and metastasis (particularly to bone). Inhibition of HER2 kinase activity abrogated the effect of Gremlin1 overexpression in vitro, suggesting a reciprocal relationship between Gremlin1 and HER2. Gremlin1 was also found to increase activity in AKT signalling and upregulates expression of PI3KCA, both important HER2 signalling pathway components. This highlights Gremlin1 as of relevance to HER2+ breast cancers, with a potential role in disease progression and response to HER2 blockade treatments