McCarthy, K.; (2005) The influence and expression of IGFBP-3 in normal and malignant breast tissue. Doctoral thesis , University of London.

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Abstract

The mitogenic and anti-apoptotic effects of insulin-like growth factor-1 (IGF-1) are regulated by a family of insulin-like growth factor binding proteins (IGFBPs), particularly IGFBP-3. In vitro studies have demonstrated the importance of the IGF-1 axis in regulating the growth of breast cancer cells. Little is known, however, about the IGF-independent role of IGFBP-3 in breast cancer and the mechanisms regulating its production. We investigated the expression of IGFBP-3 in malignant and paired adjacent normal (n=53), and healthy normal (n=17) breast tissue samples 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. Results demonstrated universal high level of expression of IGFBP-3 mRNA in all types of breast tissue. There was no difference in level of expression between any of the three groups of breast tissue (approaching those seen in the liver where it is predominantly produced). 96% of samples also expressed IGFBP-3 protein. High levels of IGFBP-3 mRNA were associated with the presence of high grade ductal carcinoma-in-situ (p<0.0001), the pre-invasive stage in breast cancer. A significant correlation was also found between IGFBP-3 negative/weakly positive tumours and lymph node negativity (p<0.05), thereby supporting an association between IGFBP-3 and the development of invasive disease. There was, however, no significant correlation 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, a marked enhancement of apoptosis was seen in breast tumours. In contrast, less apoptosis was seen in normal breast 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. It may therefore be possible in future, that IGFBP-3 levels could be used in cancer risk assessment and prevention or infact, as markers of response to cancer treatments.

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