Leptin, Adiponectin, and Sam68 in Bone Metastasis from Breast Cancer

Abstract

The most serious aspect of neoplastic disease is the spread of cancer cells to secondary sites. Skeletal metastases can escape detection long after treatment of the primary tumour and follow-up. Bone tissue is a breeding ground for many types of cancer cells, especially those derived from the breast, prostate, and lung. Despite advances in diagnosis and therapeutic strategies, bone metastases still have a profound impact on quality of life and survival and are often responsible for the fatal outcome of the disease. Bone and the bone marrow environment contain a wide variety of cells. No longer considered a passive filler, bone marrow adipocytes have emerged as critical contributors to cancer progression. Released by adipocytes, adipokines are soluble factors with hormone-like functions and are currently believed to affect tumour development. Src-associated in mitosis of 68 kDa (Sam68), originally discovered as a protein physically associated with and phosphorylated by c-Src during mitosis, is now recognised as an important RNA-binding protein linked to tumour onset and progression of disease. Sam68 also regulates splicing events and recent evidence reports that dysregulation of these events is a key step in neoplastic transformation and tumour progression. The present review reports recent findings on adipokines and Sam68 and their role in breast cancer progression and metastasis.

Intratumoral Adipocyte-High Breast Cancer Enrich for Metastatic and Inflammation-Related Pathways but Associated with Less Cancer Cell Proliferation

“…This was more evident with the ER+/HER2-subtype compared with TNBC, which indicates that the role of adipocytes is more significant with the ER+/HER2-subtype. Our result is in perfect alignment with the previous studies that leptin, one of the well-known adipokines which enhances the cell proliferation and metastasis [53,54], and leptin receptor signaling crosstalk with ER signal pathway in ER+ subtypes but not in ER-subtypes [55,56].…”

Diallyl Trisulfide Inhibits Leptin-induced Oncogenic Signaling in Human Breast Cancer Cells but Fails to Prevent Chemically-induced Luminal-type Cancer in Rats

“…Surprisingly, analysis of the breast cancer TCGA did not reveal statistically significant positive association for STAT3 expression with that of Bcl-xL, Cyclin D1, VEGF, and MMP-9 even though literature suggests regulatory function of STAT3 for these genes [11,[30][31][32][33]. The reasons for these discrepancies are not clear but may be explained by the fact that leptin can activate other signaling pathways and transcription factors [18,19,[21][22][23][24]. Nevertheless, the present study reveals that DATS inhibits constitutive as well as leptininducible expression of many pro-survival and pro-metastatic proteins leading to inhibition of cell proliferation, migration, and invasion.…”

“…Leptin is an adipokine that signals by binding to its receptor Ob-R and regulates energy balance in normal subjects [18]. Leptin has an oncogenic role in breast cancer and is one of the mechanistic links explaining obesity-breast cancer connection [19].…”

Bone Marrow Adipocytes, Adipocytokines, and Breast Cancer Cells: Novel Implications in Bone Metastasis of Breast Cancer

“…Adiponectin is reported to inhibit breast cancer growth. However, its effect may depend on the hormonal receptor status ( 109 ). In ER-negative breast cancer cells, it reduces cell growth and proliferation ( 110 ).…”

“…Leptin and adiponectin show multiple functions in regulating bone homeostasis. Leptin can enhance the secretion of soluble intercellular adhesion molecule (sICAM)-1 by breast cancer cells to induce osteoclastogenesis and accelerate bone erosion ( 109 ). On the other hand, leptin acts on bone mesenchymal stem cells (MSCs) to promote their proliferation and differentiation of MSCs into osteoblasts ( 130 ).…”