The expression and function of IGFBP-3 in normal and malignant breast tissue.
The mitogenic and anti-apoptotic effects of insulin-like growth factor-I (IGF-I) are regulated by a family of insulin-like growth factor binding proteins (IGFBPs), particularly IGFBP-3. Little is known about the IGF-independent role of IGFBP-3 in breast cancer and the mechanisms regulating its production. The expression of IGFBP-3 in paired malignant and adjacent normal (n=53), and healthy normal (n=17) breast tissue samples was investigated using RT-PCR, immunohistochemistry and ELISA. We compared IGFBP-3 expression with other members of the IGF-I axis, other known tumorigenic genes and clinicopathological parameters. We also developed a novel tissue explant system using fresh normal and malignant breast tissue, with which we examined the in vitro effects of IGFBP-3 alone and in combination with known apoptotic agent, doxorubicin (n=6), on tissue viability and apoptosis. We demonstrated a high level of expression of IGFBP-3 mRNA in all samples. 96% of samples also expressed IGFBP-3 protein. No significant correlation was seen between IGFBP-3 expression and other clinicopathological parameters. The in vitro tissue explant system demonstrated that IGFBP-3 had little effect by itself on apoptosis. However, when used in combination with doxorubicin, increased apoptosis was seen in tumours. In contrast, less apoptosis was seen in normal tissue suggesting a protective effect. These divergent effects suggest a potential novel chemotherapeutic approach in the treatment of breast cancer. These findings suggest that IGFBP-3 may play a role in tumorigenesis, and that IGFBP-3 levels could be used in the future in cancer risk assessment/prevention or as markers of response to cancer treatments.
Breast Unit, Barts and The London Queen Mary School of Medicine, London, UK. kathrynmccarthy@doctors.org.uk
K
K
McCarthy
C
C
Laban
C J
CJ
McVittie
W
W
Ogunkolade
S
S
Khalaf
S
S
Bustin
R
R
Carpenter
P J
PJ
Jenkins
D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D001940:Breast / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017154:Stromal Cells / Q000378:metabolism / Q000502:physiology; D046509:Tissue Culture Techniques; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
D014408:Biomarkers, Tumor; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D007334:Insulin-Like Growth Factor I; D004317:Doxorubicin; D051546:Cyclooxygenase 2