Clinical Science. Journal of Applied Physiology. Mero, A, Miikkulainen, H, et al. Journal of the National Cancer Institute. September 5, ;93 17 Asian Ausatralisian Journal of Animal Sciences. These products are not intended to diagnose, treat, cure or prevent any disease.
Skip to main content. Your test results may not mean you have a problem. Ask your healthcare provider what your test results mean for you. IGF-1 measurements are adjusted for age because levels tend to decrease after puberty as you get older. Normal ranges vary by age. The test is done with a blood sample. A needle is used to draw blood from a vein in your arm or hand.
Having a blood test with a needle carries some risks. These include bleeding, infection, bruising, and feeling lightheaded. When the needle pricks your arm or hand, you may feel a slight sting or pain. Afterward, the site may be sore. Malnutrition or not eating fasting will affect your results. You don't need to get ready for this test.
IGF-1 is a potent mitogen of major importance in the mammary gland. IGF-1 binding to the cognate receptor, IGF-1R, triggers a signaling cascade leading to proliferative and anti-apoptotic events. Although many of the relevant molecular pathways and intracellular cascades remain to be elucidated, a growing body of evidence points to the important role of the IGF-1 system in breast cancer development, progression and metastasis.
IGF-1 is a point of convergence for major signaling pathways implicated in breast cancer growth. In this review, we provide an overview and concise update on the function and regulation of IGF-1 as well as the role it plays in breast malignancies. IGF-1 is a key mediator of mammary terminal end bud and ductal formation during development [ 1 ]. Experimental findings have demonstrated that normal rat mammary epithelial cells continue to proliferate in serum-free media in response to IGF-1, suggesting that the IGF-1 system plays an important role in mammary gland function and maintenance [ 2 ].
In contrast, over the last two decades many studies have implicated the IGF-1 system in the development of several malignancies including breast cancer. Indeed, breast tumors may aberrantly express each component of the IGF-1 system.
To date, an increasing number of studies have attempted to elucidate the molecular mechanisms underlying the association of the IGF-1 system with breast malignancy [ 3 - 5 ]. IGF-1 is a 7. The 70 amino acid IGF-1 protein consists of four domains [ 6 ] and is produced primarily in the liver under the direct stimulation of Growth Hormone GH. IGF-1 gene expression is controlled by both transcriptional and post-translational modifications.
Distinct IGFpeptides may arise via the utilization of different promoters, alternative splicing, proteolytic processing and glycosylation events [ 7 ]. IGF-1 is expressed in almost every human tissue. In both normal mammary gland and malignant breast tissues, IGF-1 is mainly expressed by stromal and only rarely by epithelial cells [ 8 ].
The mitogenic, anti-apoptotic and other effects of IGF-1 protein are mainly mediated by the transmembrane tyrosine kinase receptor IGF-1R, which in contrast to IGF-1, is mainly expressed in the mammary epithelium.
Notably, the IRS-1 has been found to be overexpressed in primary breast tumors [ 12 ]. Breast Cancer BrCa remains one of the leading causes of cancer-related death worldwide. The heterogeneity and variability in treatment and survival response, underscore the need to elucidate the biological mechanisms driving BrCa.
A proposed molecular profile approach for breast tumor classification defines distinct molecular subtypes of the disease based on differences in the expression patterns of estrogen receptor ER , progesterone receptor PR and HER2 ERBB2 [ 15 ]. Although BrCa has been intensely studied and multiple reported biomarkers and molecular targets have been reported in the literature, only a few are of proven relevance to routine clinical practice.
Both in vitro and in vivo models, as well as clinical and epidemiological data have indicated the role of the IGF-1 system in BrCa via many diverse endocrine, paracrine and autocrine signaling pathways [ 16 , 17 ]. Although some of these findings are conflicting, many components of the IGF-1 system are known to be altered during BrCa establishment and progression [ 9 , 16 , 18 ].
Since the initial report by Peyrat et al. This finding is also supported by the data analysis from the European Prospective Investigation into Cancer and Nutrition cohort [ 21 ]. In contrast no correlation was found between IGF-1 levels and breast cancer development in a cohort of Brazilian women [ 23 ] or women during early pregnancy [ 24 ].
Mammographic density is one of the strongest predictors of breast cancer development and may be associated with serum IGF-1 levels in premenopausal women. Dorio et al. The association of IGF-1 with disease prognosis following tumor establishment is also currently under investigation.
High circulating IGF-1 levels have been positively correlated with bad prognosis in patients undergoing endocrine therapy [ 28 ], while another study found that high serum IGF-1 is associated with increased all-cause mortality in a cohort of women with established breast malignancy [ 29 ]. Further studies measuring both mRNA and protein levels are warranted, in order to better delineate the role of circulating IGF-1 in disease risk and progression.
Over the last decade, there has been increasing interest in the studying of the genomic analysis of the IGF-1 gene for specific alterations involved in cancer formation and progression. One of the most studied genetic variations of IGF-1 is a polymorphic sequence of repeating cytosine-adenine dinucleotides CA ranging from 10 to 24 repeats in length, with the CA 19 being the most common allele. This repeating sequence is located almost 1 kb upstream of the transcription initiation site and is thus considered to be a promoter polymorphism likely implicated in regulating IGF-1 protein levels.
No significant association has been found between CA 19 and BrCa risk among Arab Omani women in both post- and pre-menopausal status [ 30 ]. No association between CA 17, 19 and 20 alleles and breast cancer risk was found in a meta-analysis by Huang et al. Indeed, there is growing evidence that the CA 19 allele is associated with increased incidence of breast and other cancers in Asians [ 34 ]. Allelic length has also been found to correlate with disease development.
BrCa risk is increased in Iranian women carrying two alleles of CA longer than 19 and decreased in those carrying two alleles shorter than 20 [ 35 ]. Most of the SNPs studied are in areas located in highly evolutionary conserved regions ECR near to the transcription factor binding domains BD , thereby affecting transcription regulation.
Biong et al. In addition other large collaborative studies using data from the BPC3, genotyped a total of SNPs in a sample size of more than 5, Caucasian women and detected a clear association between genetic variations of IGF-1 and plasma IGF-1 levels but no association with BrCa risk [ 40 ].
Despite the large number of studies identifying IGF-1 gene polymorphisms in association with BrCa risk, only a few have investigated the relationship of such polymorphisms with disease progression. This is in contrast to other studies described above, which use genetic variants of IGF-1 as candidate risk factors. This finding was further supported by microarray analysis of tumor samples revealing increased IGF-1 expression in a specific BrCa subtype associated with better prognosis [ 45 ].
The contradictory role of circulating and tissue IGF-1 may be partially explained by clinical data showing a lack of correlation between circulating and tissue IGF-1 levels [ 46 ].
Several factors could explain this discrepancy. Thus, tissue IGF-1 levels may be a better marker of tumor IGF-1 expression compared to serum levels, as has already been established in mammary gland branching morphogenesis [ 47 ]. Within tissue microenvironment, increased IGF-1 levels may reflect cell differentiation into a less aggressive phenotype.
Ethnic and other differences among the different groups studied may also account for these conflicting results. Future investigation should focus on specific ethnic groups, measure IGF-1 levels in both serum and breast tissue of the same patient and correlate those findings with disease risk and outcome factors.
In addition to the above epidemiological findings, many pre-clinical laboratory studies have focused on the impact of IGF-1 in cancer cell proliferation, migration, tumor growth and metastasis using in vitro and in vivo models to identify the signaling pathways involved in these processes.
IGF-1 release from differentiated or precursor adipocytes derived from obese patients was two fold higher compared to lean individuals. It also induced the proliferation of MCF7 cells in co-culture experiments, further supporting the notion that obesity per se could contribute to BrCa progression [ 49 ]. Microarray analysis in an ex vivo model of primary breast fibroblasts derived from BrCa patients revealed a signature of genes associated with proliferation following stimulation with IGF-1 [ 50 ].
An earlier study suggested that IGFmediated stimulation of proliferation might act through transcriptional regulation [ 51 ]. Administration of IGF-1 induces invasion of MDA-MB BrCa cells via the formation of cellular protrusions called lamellipodia, a characteristic projection at the front edge of motile cells believed to function as the motor pulling the cell forward during cell migration [ 52 ].
In vivo findings also indicate a tumor-promoting role of IGF MCF-7 cells stably overexpressing IGF-1 induce significantly higher tumor volumes compared with control or mock cells in mouse xenografts [ 51 ]. It is also well known that autocrine IGF-1 signaling affects mammary development. Indeed, conditional and epithelial-specific knockout of IGF-1 results in reduced mammary branching during ductal growth [ 53 ].
Targeting IGF-1 in mammary epithelium will clarify the role of autocrine IGF-1 signaling in neoplastic transformation of breast epithelium. Future studies should focus on this approach. Recent research efforts have used animal models to delineate the impact of IGF-1 in complex disease events including metabolic regulations, angiogenesis and metastasis. Transgenic mice specifically overexpressing IGF-1 in mammary epithelium demonstrate upregulation of the Vascular Endothelial Growth Factor VEGF , a pro-angiogenic factor, in prepubertal glands and induction of cyclooxygenase-2 COX-2 , an inflammatory molecule that is also associated with angiogenesis and is responsible for formation of prostaglandin PG , [ 55 ].
It is also well established that caloric restriction prevents mammary tumorigenesis in rodents. Furthermore, the effect of caloric restriction in IGF-1 levels may regulate luminal tumor growth by modulating the epithelial-mesenchymal transition EMT process and chemokine milieu [ 57 ].
This pathway appears to be involved in the metastasis of breast tumors. Bone is one of the most common distant target sites for BrCa metastasis. Hiraga et al. The fact that IGF-1 is mostly expressed by stroma underscores the significance of the interplay between stroma and epithelium dururing IGF-1 paracrine signaling resulting in disease establishment and progression. The excess of paracrine IGF-1 signaling via stromal production may trigger epithelial IGF-1 expression, leading to a more malignant phenotype.
Within the epithelium, aberrant IGF-1 autocrine signaling could further contribute to disease aggressiveness. Future studies should focus on clarification of the paracrine role of IGF-1, in establishment and progression of breast carcinoma, via in vivo models specifically overexpressing or lacking IGF-1 in stroma. The IGF-1 role in breast cancer. IGF-1 is mostly secreted by stromal cells and acts through paracrine signaling to adjacent epithelial tumor cells and vice versa.
Once the disease is well established within the primary breast tumor microenvironment, IGF-1 autocrine within epithelium and endocrine via the systemic circulation activity facilitates disease progression and metastasis respectively. Within the new tumor location, the interplay between metastasized breast cancer cells and host tissue cells, drive the last to a more cancerous phenotype via IGF-1 paracrine signaling.
In addition, aberrant IGF-1 expression by host tissue cells supports BrCa proliferation via autocrine signaling. Furthermore, plasma IGFBP 3 levels have been shown to be independent of mammographic density, which is a well-established BrCa risk factor [ 26 , 27 ].
Recent studies did not detect a significant association between plasma IGFBP 3 and overall survival or risk of all-cause mortality [ 28 , 29 ]. Hensch et al. The postulated correlation is thought to be, due to enhanced promoter activity, indicating a regulation in cis [ 40 , 64 ].
Although the exact mechanism needs to be elucidated, in vitro experiments indicate that IGFBP 3 inhibits BrCa proliferation and induces apoptosis. It has also been found to be associated with lymph node metastasis in BrCa cells [ 67 ]. Consequently, several studies have indicated a correlation of IGF-1R expression with disease development [ 70 , 71 ].
Once cancer has been established, the importance of IGF-1R for disease progression remains unclear. Furthermore, many studies indicate a down-regulation of IGF-1R upon cancer progression, whereas others report elevated levels in metastatic stages. Increased tissue IGF-1R mRNA levels strongly correlate with poor patient clinical outcomes across different molecular BrCa subtypes [ 73 ], whereas IGF-1R is highly expressed in patients with early BrCa and overall positively associated with good prognostic variables.
Several studies have attempted to clarify the relationship between specific genetic variants of IGF-1R and disease development and progression.
Although a wealth of evidence supports the key role of miRNAs in several tumorigenic processes, only a few studies have evaluated the potential association between polymorphisms in miRNA binding sites and cancers. Gilam et al. Future studies may apply a Mendelian randomization approach to elucidate the association between functional IGF-1R polymorphisms and BrCa risk.
Propelled by the data accumulated by miRNA approaches, researchers are now focusing on elucidating the molecular mechanisms underlying the gene regulation of IGF-1R. Recent studies have provided new insights into the molecular functions and biological significance of IGF-1R in BrCa by suggesting the role of novel transcription factors and mechanisms implicated in IGF-IR regulation. Several other molecules have been involved in these processes. Using a novel DNA affinity chromatography, Sarfstein et al.
Of note, two independent groups simultaneously reported in that IGF-1R undergoes nuclear translocation in human cancers, indicating that IGF-1R itself may act as a transcription factor [ 88 , 89 ]. This enhances the activity of the promoter and thus IGF-1R acts as a transcriptional auto-activator [ 3 ]. The IGF-1 receptor auto- regulation mechanism in breast cancer.
An important area for future research will be to clarify the role of IGF-1R expression and downstream signaling pathways in different BrCa molecular subtypes.
Whereas basal-like tumors frequently have mutations of p53 gene and therefore induce IGF-1R transcriptional upregulation, claudin-low subtypes frequently underexpress IGF-1R and closely resemble mammary epithelial stem cells expressing many of the EMT markers.
Indeed, studies in transgenic mice reveal that epithelial-specific overexpression of IGF-1R induces mammary tumors with basal-like characteristics whereas epithelial-specific down-regulation of IGF-1R produces tumor with a more claudin-low molecular profile [ 91 ].
The same team has previously reported that doxycycline-induced downregulation of IGF-1R in mammary epithelium using the same animal model induced tumor regression [ 92 ]. The importance of steroids and especially the ER status in disease progression is well established. Its significance is further supported by the fact that anti-estrogens, such as tamoxifen are routinely used in BrCa treatment. Crosstalk between growth factors and estrogens may be responsible for the development of estrogen-independent BrCa tumors [ ].
BrCa cells have a differential response to IGF-1 with regards to both proliferation and survival depending on their ER status. The mechanism underlying this cross-talk may be particularly important for the development of combination treatment strategies. Becker et al. Aromatase is a key enzyme during estrogen biosynthesis and is routinely used as a therapeutic target in ER positive BrCa tumors.
Thus, IGF-1 pathways can enhance aromatase activity via post-transcriptional modifications that do not affect aromatase protein levels [ ]. MCF7 cells engineered to express reduced levels of IGF-1R demonstrate decreased proliferation and increased apoptosis in response to E2 compared to controls. It has been demonstrated that in vitro E2 and IGF-1 co-regulate a number of genes comprised mainly of tumor suppressing factors associated with poor disease outcome.
E2 can also induce IGF-1R expression in mouse xenograft models [ , ]. Tian et al. Although the exact mechanism is not clear, estrogens may be modulated by the IGF-1 system via both transcriptional and post-transcriptional mechanisms leading to increased BrCa proliferation and growth through activation of the IGF-1 signaling pathways Figure 3.
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