Insulin-Like Growth Factor (IGF)-I and IGF-II Serum Concentrations in Patients with Benign and Malignant Breast Lesions

Singer, Christian F.; Mogg, Maurice; Koestler, W.; Pacher, Martina; Márton, Erika; Kubista, E.; Schreiber, Martin

doi:10.1158/1078-0432.ccr-03-0093

Cited by 31 publications

(27 citation statements)

References 38 publications

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“…Several growth factors such as IGFs (31)(32)(33), epidermal growth factor (34,35), and transforming growth factor h (36) have been reported to modulate breast and lung carcinoma cell proliferation. Among them, however, IGF-I and IGF-II are considered to be the most potent mitogens for carcinoma cells (31,37,38). In the present study, we have provided in vitro and in vivo data that the IGF-I-induced proliferation of MDA-MB231 cells is significantly inhibited by treatment with KB-R7785, neutralizing anti-ADAM28 antibody, or transfection with ADAM28 siRNA, and that injection of ADAM28 siRNA to the MDA-MB231 cell xenografts significantly suppresses tumor growth.…”

Section: Discussionmentioning

confidence: 99%

ADAM28 Is Overexpressed in Human Breast Carcinomas: Implications for Carcinoma Cell Proliferation through Cleavage of Insulin-like Growth Factor Binding Protein-3

Mitsui

Mochizuki²,

Kodama³

et al. 2006

Cancer Research

112

134

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A disintegrin and metalloproteinases (ADAMs) are involved in various biological events including cell adhesion, cell fusion, membrane protein shedding, and proteolysis. In the present study, our reverse transcription-PCR analysis showed that among the 12 different ADAM species with a putative metalloproteinase motif, prototype membrane-anchored ADAM28m and secreted-type ADAM28s are selectively expressed in human breast carcinoma tissues. By real-time quantitative PCR, their expression levels were significantly higher in carcinomas than in nonneoplastic breast tissues. In situ hybridization, immunohistochemistry, and immunoblotting analyses indicated that ADAM28 is predominantly expressed in an active form by carcinoma cells within carcinoma tissues. A direct correlation was observed between mRNA expression levels and proliferative activity of the carcinoma cells. Treatment of ADAM28-expressing breast carcinoma cells (MDA-MB231) with insulin-like growth factor-I (IGF-I) increased cell proliferation, cleavage of IGF binding protein (IGFBP)-3, as well as IGF-I cell signaling; these processes were all significantly inhibited by treatment with ADAM inhibitor or anti-ADAM28 antibody. Down-regulation of ADAM28 expression in MDA-MB231 cells with small interfering RNA significantly reduced cell proliferation, IGFBP-3 cleavage, and growth of xenografts in mice. In addition, cleavage of IGFBP-3 in breast carcinoma tissues was correlated with ADAM28 expression levels and inhibited by treatment with ADAM inhibitor or anti-ADAM28 antibody. These results show that ADAM28 is overexpressed in an activated form in human breast carcinoma cells and suggest that ADAM28 is involved in cell proliferation through enhanced bioavailability of IGF-I released from the IGF-I/ IGFBP-3 complex by selective IGFBP-3 cleavage in human breast carcinomas.

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Section: Discussionmentioning

confidence: 99%

ADAM28 Is Overexpressed in Human Breast Carcinomas: Implications for Carcinoma Cell Proliferation through Cleavage of Insulin-like Growth Factor Binding Protein-3

Mitsui

Mochizuki²,

Kodama³

et al. 2006

Cancer Research

112

134

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“…This was not observed, possibly due to the small tumour size and range of sizes in the present study. One study found a correlation between circulating free IGF2 and breast tumour size, but surprisingly cancer patients showed lower levels of free IGF2 than matched controls, and noteworthy, these findings only became evident after correcting for the changes in body fluid composition in the post-operative state (10).…”

Section: Discussionmentioning

confidence: 99%

“…In vivo evidence includes several large prospective studies and in general they suggest a modestly increased breast cancer risk in individuals with serum total IGF1 levels within the upper normal range (5,6). Some studies have investigated the molar ratio of IGF1 to IGFBP3 (a putative marker of free IGF1) in breast cancer (7), whereas only a few studies include direct analysis of free IGF1 (6,(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Elevated free IGF2 levels in localized, early-stage breast cancer in women

Espelund

Cold²,

Frystyk³

et al. 2008

European Journal of Endocrinology

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Objective: Epidemiological studies imply an association between circulating IGF1 and breast cancer, whereas the role of IGF2, which also acts on the IGF1 receptor, is less settled. This study investigates the association between IGF2 and breast cancer in patients with localized disease. Design: The participants were women with well-characterized, early stage, localized breast cancer (nZ43) and matched healthy women (nZ38), from whom fasting serum levels of IGF-related peptides were measured. Results: In patients, mean free IGF2 was increased (C57%, P!0.001), in spite of reduced total IGF2 levels (K12%, PZ0.003) when compared with controls. Similar changes were seen in free IGF1 (C28%, PZ0.004) and total IGF1 (K16% PZNS). Pro-IGF2 and IGF-binding protein 1 (IGFBP1) were unchanged. IGFBP2 was reduced by 22% in the patients (PZ0.004). The patients showed reduced IGFBP3 protease activity and accordingly increased levels of intact IGFBP3, whereas total IGFBP3 was unchanged. Conclusion: Women with localized, early-stage breast cancer show elevated circulating free IGF1 and IGF2, reduced total IGF2 and alterations in IGFBPs. The changes observed despite minimal cancer disease suggest a role for the circulating IGF system in the progression of breast cancer in women.European Journal of Endocrinology 159 595-601

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“…The synthesis of IGFs in adults predominantly occurs in the liver but may also be accomplished by other tissues, since liver-specific disruption of the IGF-I gene has been demonstrated not to affect growth development and maturation in mice (Liu et al 1993, Yakar et al 1999. Several studies have investigated the systemic and tumoral expression of IGF family members in sporadic breast cancer patients and found elevated IGF levels in patients with breast cancer (Peyrat et al 1993, Rocha et al 1997, and a positive correlation with breast tumor size (Singer et al 2004). However, data on the tumoral expression of members of the IGF axis in patients with inherited breast tumors are sparse, and have not been demonstrated to influence systemic IGF-I levels.…”

Section: Introductionmentioning

confidence: 99%

Intratumoral IGF-I protein expression is selectively upregulated in breast cancer patients with BRCA1/2 mutations

Hudelist

Wagner²,

Rosner³

et al. 2007

Endocrine Related Cancer

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BRCA1/2 mutations predispose to early onset breast and ovarian cancers. The phenotypic expression of mutant alleles, however, is thought to be modified by factors that are also involved in the pathogenesis of sporadic breast cancer. One such protein is IGF-I, one of the strongest mitogens to breast cancer cells in vitro. We have utilized immunohistochemistry to compare the intratumoral IGF-I and IGF-I receptor (IGF-IR) protein expression in 57 BRCA1/2 mutation carriers and 102 matched breast cancer patients without a family history in a nested case-control study. BRCA1 silencing by siRNA was used to investigate the effect of BRCA mutations on IGF-I protein expression. IGF-I protein expression was detected in tumoral epithelium and surrounding stroma, and was significantly upregulated in tumors of BRCA mutation carriers when compared with matched sporadic tumors (epithelial: 87.7% vs 61.8%, PZ0.001; stromal: 73.7% vs 34.3%, P!0.001). By contrast, IGF-IR protein expression was confined to malignant epithelium and was unchanged in mutation carriers (52.6% vs 39.2%, PZ0.310). While in mutation carriers IGF-IR protein expression was significantly correlated with both epithelial (PZ0.003) and stromal IGF-I (PZ0.02), this association was less pronounced in sporadic breast cancer (PZ0.02 respectively). siRNA-mediated downregulation of BRCA1 in primary human mammary gland cells triggered upregulation of endogenous intracellular IGF-I in vitro. The increased intratumoral IGF-I protein expression in BRCA mutation carriers suggests an involvement of the IGF-I/IGF-IR axis in the biological behavior of breast cancers in this population and could define a potential therapeutic target.

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Insulin-Like Growth Factor (IGF)-I and IGF-II Serum Concentrations in Patients with Benign and Malignant Breast Lesions

Cited by 31 publications

References 38 publications

ADAM28 Is Overexpressed in Human Breast Carcinomas: Implications for Carcinoma Cell Proliferation through Cleavage of Insulin-like Growth Factor Binding Protein-3

ADAM28 Is Overexpressed in Human Breast Carcinomas: Implications for Carcinoma Cell Proliferation through Cleavage of Insulin-like Growth Factor Binding Protein-3

Elevated free IGF2 levels in localized, early-stage breast cancer in women

Intratumoral IGF-I protein expression is selectively upregulated in breast cancer patients with BRCA1/2 mutations

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