IGFBP2 and IGFBP5 Overexpression Correlates With the Lymph Node Metastasis in T1 Breast Carcinomas

Wang, Huamin; Arun, Banu; Wang, Hua; Fuller, Gregory N.; Zhang, Wei; Middleton, Lavinia P.; Şahin, Ayşegül

doi:10.1111/j.1524-4741.2008.00572.x

Cited by 53 publications

(51 citation statements)

References 20 publications

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“…Studies on IGFBP2 expression in breast tumor tissue are still limited in number. The reports regarding the correlation between IGFBP2 and ER expression are contradictory (9)(10)(11)(12). Few studies investigated the prognostic effect of IGFBP2.…”

Section: Discussionmentioning

confidence: 99%

“…Much less is known about the prognostic relevance of autocrine and paracrine IGF signaling in tumor tissue. Several breast cancer studies reported on the correlation between estrogen receptor (ER) status and the expression patterns of IGF-related proteins (9)(10)(11)(12), but only few also evaluated the effect of IGF-related mRNA or protein expressions in tumor tissue on survival (9,(13)(14)(15)(16)(17)(18)(19)(20)(21).…”

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confidence: 99%

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IGFBP2 and IGFBP3 Protein Expressions in Human Breast Cancer: Association with Hormonal Factors and Obesity

Probst‐Hensch

Steiner

Schraml

et al. 2010

Clinical Cancer Research

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Purpose: The insulin-like growth factor (IGF) signaling system is involved in breast cancer initiation and progression. The prognostic relevance of tumor expression patterns of IGFI-related proteins remains poorly understood. This study associates the expression of selected IGF proteins with breast tumor and patient characteristics.Experimental Design: IGFI, IGFI receptor, IGF-binding protein (IGFBP)2, and IGFBP3 expression was measured in 855 primary breast carcinomas by immunohistochemistry using tissue microarrays. We investigated the association of tumor and nodal stage, grade, hormone receptor status, HER2 gene amplification, menopausal status, body mass index, and survival with IGF protein expression.Results: In contrast to IGFI, the expression of IGFI receptor, IGFBP2, and IGFBP3 was associated with estrogen receptor status. In addition, IGFBP3 was positively correlated with body mass index and premenopausal status. Importantly, IGFBP2 was an independent and positive predictor of overall survival (hazard ratio, 0.48; 95% confidence interval, 0.24-0.95; P = 0.04). There was a weak suggestion for IGFBP2 and overweight to modify each other's effect on survival.Conclusions: According to these results, which need confirmation in larger patient series, the prognostic relevance of IGFBP2 and IGFBP3 protein expressions in breast cancer may depend on the hormonal context and body weight. Clin Cancer Res; 16(3); 1025-32. ©2010 AACR.Understanding the biology of breast cancer progression is an important aspect of identifying therapeutic targets. Both obesity at diagnosis and subsequent weight gain are predictive of worse breast cancer survival (1). The obesity-breast cancer association may in part be related to hyperinsulinemia, the concomitant decrease in insulin-like growth factor (IGF)-binding proteins (IGFBP)1 and IGFBP2, and the resulting increase in bioactive IGFI (2). IGFI and IGF2 play a role in mammary gland development (3-5). They have mitogenic, antiapoptotic, and proangiogenic effects and stimulate the motility of breast cancer cells in vitro (3). The two growth factors act through IGFI receptor (IGFIR) homodimerization (3). Their bioavailability in circulation and tissues is regulated by at least six IGF-binding proteins. IGFBP3 and IGFBP2 are the most abundant IGFBPs in the blood. In addition to regulating IGF activity, IGFBPs exert additional IGF-independent effects (6).Transgenic mice deficient in IGFI exhibit a decreased susceptibility to mammary carcinogens (7). Tumor incidence is increased in mice expressing IGFI or IGF2 in the mammary gland (3). According to several meta-analyses and systematic reviews, circulating concentrations of IGFI and less consistently of IGFBP3 were positively associated with premenopausal breast cancer (8). Much less is known about the prognostic relevance of autocrine and paracrine IGF signaling in tumor tissue. Several breast cancer studies reported on the correlation between estrogen receptor (ER) status and the expression patterns of IGF-related proteins (9-12...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

IGFBP2 and IGFBP3 Protein Expressions in Human Breast Cancer: Association with Hormonal Factors and Obesity

Probst‐Hensch

Steiner

Schraml

et al. 2010

Clinical Cancer Research

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“…This result is likely considering the report by Hu et al (31), where a yeast two-hybrid screen of a random peptide library identified a number of putative proteins that may interact with PDZK1; however, Akt, Her2/Neu and EGFR were not among the candidates. Interestingly, other factors known to be involved in cell proliferation and signaling in breast cancer were identified in their screen, such as cyclin-dependent kinase 4 (CDK4) and insulin-like growth factor-binding protein 5 (IGFBP5) (32,33). PDZK1 function appears to be tissue-specific because gene deletion has been shown to completely inhibit SR-B1 expression exclusively in the liver, which explains the proatherogenic phenotype observed in PDZK1 knockout mice (14,34).…”

Section: Discussionmentioning

confidence: 99%

Correlation between PDZK1, Cdc37, Akt and Breast Cancer Malignancy: The Role of PDZK1 in Cell Growth through Akt Stabilization by Increasing and Interacting with Cdc37

Kim

Elmageed

Davis

et al. 2014

Mol Med

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PDZ domain containing 1 (PDZK1) is a scaffold protein that plays a role in the fate of several proteins. Estrogen can induce PDZK1 gene expression; however, our recent report showed that PDZK1 expression in the breast cancer cell line MCF-7 is indirect and involves insulin-like growth factor (IGF)-1 receptor function. Such a relationship was established in cell culture systems and human breast cancer tissues. Here we show that overexpression of PDZK1 promoted an increase in cyclin D1 and enhanced anchorageindependent growth of MCF-7 cells in the absence of 17β-estradiol, suggesting that PDZK1 harbors oncogenic activity. Indeed, PDKZ1 overexpression enhanced epidermal growth factor receptor (EGFR)-stimulated MEK/ERK1/2 signaling and IGF-induced Akt phosphorylation. PDZK1 appeared to play this role, in part, by stabilizing the integrity of the growth promoting factors Akt, human epidermal growth factor receptor 2 (Her2/Neu) and EGFR. Increased Akt levels occurred via a decrease in the ubiquitination of the kinase. PDZK1 overexpression was associated with resistance to paclitaxel/5-fluorouracil/etoposide only at low concentrations. Although the increased stability of Akt was sensitive to heat shock protein 90 (HSP90) inhibition, increased levels of the cochaperone cell division cycle 37 (Cdc37), as well as its ability to bind PDZK1, appear to play a larger role in kinase stability. Using human tissue microarrays, we show strong positive correlation between PDZK1, Akt and Cdc37 protein levels, and all correlated with human breast malignancy. There were no positive correlations between PDZK1 and Cdc37 at the mRNA levels, confirming our in vitro studies. These results demonstrate a relationship between PDZK1, Akt and Cdc37, and potentially Her2/Neu and EGFR, in breast cancer, representing a new axis that can be targeted therapeutically to reduce the burden of human breast cancer.

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“…37 Furthermore, the overexpression of IGFBP2 and IGFBP5 are associated with the progression of breast cancer. 38 These reports indicate that lifestyle changes may modulate the IGF-IGFBP signaling contributing to the development of chronic diseases such as obesity, insulin resistance and cancer. This is the first report on the association between genetic variations of the IGFBP5 gene and adiponectin.…”

Section: Discussionmentioning

confidence: 99%

Association of sequence variations in the gene encoding insulin-like growth factor binding protein 5 with adiponectin

Kallio

Kolehmainen

et al. 2008

Int J Obes

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Background: Insulin-like growth factor binding protein 5 (IGFBP5) binds to IGF and thus modulates IGF signaling pathway. We have shown earlier that the IGFBP5 gene was downregulated in the adipose tissue after 12-week carbohydrate diet with low insulinemic response. Objective: The aim was to examine the putative contribution of genetic variation of the IGFBP5 gene to the characteristics of metabolic syndrome and incidence of type 2 diabetes (T2DM) in the Finnish Diabetes Prevention Study (DPS). Methods: DPS is a longitudinal study where 522 subjects with impaired glucose tolerance were randomized to either lifestyle intervention group or control group. DNA was available from 507 subjects (mean body mass index (BMI) 31.2±4.5 kg/m 2 , age 55 ± 7 years). The eight single-nucleotide polymorphisms (SNPs) were selected from HapMap database and genotyped by Taqman allelic discrimination protocol. The main results were confirmed in a larger cross-sectional study population (METSIM). In addition, the gene expression of IGFBP5 was studied in two previously published study populations (FUNGENUT and GENOBIN) of 124 subjects with insulin resistance (BMI 32.2 ± 3.5 kg/m 2 , age 57.7 ± 7.4 years). Results: Three out of eight IGFBP5 markers (rs9341234, rs3276 and rs11575134) were significantly associated with circulating adiponectin concentrations in men. Furthermore, mRNA expression studies of subcutaneous adipose tissue showed that mRNA concentrations of IGFBP5 correlated with adiponectin concentrations in all subjects and in women. None of the IGFBP5 SNPs were associated with T2DM. Conclusions: Our findings show that IGFBP5 has a gender-specific association with adiponectin, which may modulate the development of metabolic syndrome.

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IGFBP2 and IGFBP5 Overexpression Correlates With the Lymph Node Metastasis in T1 Breast Carcinomas

Cited by 53 publications

References 20 publications

IGFBP2 and IGFBP3 Protein Expressions in Human Breast Cancer: Association with Hormonal Factors and Obesity

IGFBP2 and IGFBP3 Protein Expressions in Human Breast Cancer: Association with Hormonal Factors and Obesity

Correlation between PDZK1, Cdc37, Akt and Breast Cancer Malignancy: The Role of PDZK1 in Cell Growth through Akt Stabilization by Increasing and Interacting with Cdc37

Association of sequence variations in the gene encoding insulin-like growth factor binding protein 5 with adiponectin

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