IGFBP1, secreted by hepatoma and other cell types in various phosphorylated forms, mainly functions in the intracellular and pericellular compartments to regulate cell growth and survival. It interacts with several other proteins in addition to ligands IGFs and plays an important role on the development and progression of several cancer types.[3,16–18] Previous studies have investigated the association between circulating IGFBP1 levels and breast cancer. Kaaks et al reported that reduced levels of IGFBP1 were associated with increased breast cancer risk, possibly by the anti-tumor effects of IGFBP1. IGFBP1 appears to modulate the anti-apoptotic effects of IGF-1 through IGF-dependent and -independent mechanisms in human breast cancer. In addition, IGFBP1 has an influence on survival, which mechanically depends on inhibiting breast cancer cell motility and the known favorable effect of insulin.[21,22] However, Krajcik et al's study showed IGFBP1 level was not associated with the incidence of breast cancer in either pre- or postmenopausal women. In the present study, we found that the high expression of IGFBP1 mRNA was significantly correlated to favorable RFS for all breast cancer patients. This heterogeneity might be related to variability in clinicopathological features of breast cancer patients.
In terms of IGFBP3, there is no consistent evidence for an association between serum IGFBP3 levels and the prognosis of breast cancer. Several studies indicated that the risk of death was increased in breast cancer patients with higher IGFBP3 levels,[33–37] and this relevance was independent of other prognostic markers. However, serum IGFBP3 concentration was not prognostic role for outcome in breast cancer has also been reported.[38,39] On the contrary, Mu et als study suggested that serum IGFBP3 level was associated with favorable survival in breast cancer patients. Specifically, our study exhibits that the high expression of IGFBP3 mRNA was significantly correlated to worsen RFS, but not to OS, DMFS, and PPS. The possible explanation for these results may be the variation of enrolled subjects’ disease state, such as differentiation grade, lymph node status, or TP53 status.
In accordance with the present results, IGFBP4 expression is positively correlated with ER status in mammary tumors.[41,42] In vitro, IGFBP4 inhibited estradiol-triggered growth of MCF-7 cells through Akt/PKB signaling pathway. In breast cancer population, the high expression of IGFBP4 was correlated to favorable prognosis for ER-positive patients, which may serve as an independent prognostic marker in breast cancer. Recently, pregnancy-associated plasma protein-A (PAPP-A) holds a great attention for IGF system. PAPP-A is a metalloproteinase that is able to specifically cleave IGFBP4, resulting in reduced affinity for IGFs. Consequently, serum PAPP-A level may be associated with prognosis of breast cancer patients.
IGFBP5 is the most evolutionarily conserved member in a family of 6 high-affinity IGFBPs.[45,46] it plays a certain role in apoptosis and proliferation in breast cancer cell, possibly mediated by IGF-independent, cytostatic and cytotoxic effects. Mita et al reported that low expression of IGFBP-5 was associated with better-prognosis for ER-positive breast cancer patients. Similarly, overexpression of IGFBP5 was associated with poor survival in breast cancer patients with positive lymph nodes and negative ER, which is consistent with our results. In addition, Hermani's study showed IGFBP5 strongly decreased estradiol-triggered growth of breast cancer cells. Taking together, IGFBP5 may considered to be a positive prognostic marker in breast cancer.
The role of IGFBP6 has been widely investigated in other solid tumors; however, it remains unexplored in breast cancer. It is established that IGFBP6 level is lower in tumor tissue than normal cells, implying an anti-tumor effect on cancer patients. In the present study, we found the high expression of IGFBP6 mRNA was significantly correlated to favorable OS, RFS, and PPS for all breast cancer. These paradoxical results may be explained by heterogeneity in cancer.
It is noteworthy that the high expression of IGFBP4 mRNA was significantly associated with favorable OS for ER positive breast cancer patients in our study. The cross talk between IGFBP and estrogen-signaling pathway plays a certain role in human breast cancer. On one hand, IGF is able to trigger the proliferative signal in breast cancer cells in concert with estrogen. On the other hand, estrogen can also modulate IGFBPs gene expression and the ER status of human breast cancer cells. Furthermore, IGFBPs inhibit estrogen-dependent growth of MCF-7 breast cancer cells.
The IGF signaling pathway has been associated with both initiation and progression of breast cancer. The majority of biological effects of IGF signaling are mediated by IGF receptors. IGFBPs, have greater affinity for binding to the IGFs than the IGF receptors, were originally characterized as passive reservoirs of circulating IGFs. IGFBPs have many actions beyond their endocrine role in IGFs transport. They also function in the pericellular and intracellular compartments to regulate cell growth and survival via interacting with lots of proteins, in addition to IGFs. Intranuclear roles of IGFBPs in transcriptional regulation, induction of apoptosis and DNA damage repair point to their intimate involvement in tumor development and progression. Two parts of IGFBPs may interact with each other to regulate cell proliferation, differentiation, and apoptosis. However, the possible relationship between circulating and tumor IGFBPs is still not very clear. Moreover, the interaction of IGFBPs with breast cancer can be either inhibitory or stimulatory.
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