The Association Between Serum Igf1 And Breast Cancer Risk

Many studies support the role of IGF-1 in malignant transformation of breast epithelia. Animal studies have shown that transgenic mice which over-express growth hormone and IGF-1 exhibit an increased rate of developing mammary tumours (46, 47). Likewise, liver-IGF-1-deficient mice showed a 75% reduction of circulating IGF-1 compared to control mice which also correlated with a significant reduction in risk of mammary tumour development (48) while treatment of primates with growth hormone and IGF-1 led to mammary gland hyperplasia (49). Animal studies suggested that high levels of circulating IGF-1 could be responsible for an increased risk of breast cancer in humans and this hypothesis prompted studies looking at the relationship between serum IGF-1 and risk of breast cancer in human subjects.

The first prospective study on this relationship was performed by Hankinson et al. (18) who carried out a case-control study by retrospectively measuring serum IGF-1 on blood samples collected from 397 women who subsequently developed breast cancer against 620 age-matched controls. The results showed that when looking at the overall group, there was no relationship between serum IGF-1 and risk of developing breast cancer. However, on sub-analysis based on menopausal status, there was a significant association between elevated serum IGF-1 and breast cancer risk in women who were premenopausal at the time of blood collection (50). A subsequent larger case-control study by Schernhammer et al. involving 800 breast cancer patients and 1,129 age-matched controls also showed that serum IGF-1 levels were modestly associated with an increased breast cancer risk among premenopausal women only (45, 51). Other studies have confirmed that this risk was not present in postmenopausal women with high serum IGF-1 levels (52-58). One study which examined postmenopausal women alone did show a significant association between high serum IGF-1 levels and a risk of breast cancer but this was not significant once the hormone replacement therapy users were removed from the series (59). A meta-analytical study by Shi et al. involving 16 similar studies has concluded that there is a nearly 40% increase in breast cancer risk among premenopausal women with higher IGF-1 in circulation (53, 60). These findings reinforce the understanding that oestrogen may act as a cofactor in promoting the effects of IGF-1 on normal breast cells and may lead to malignant transformation.

6. THE ASSOCIATION BETWEEN SERUM IGF-1 LEVELS WITH CLINICOPATHOLOGICAL FACTORS, DISEASE-FREE SURVIVAL, AND OVERALL SURVIVAL

Many studies have confirmed that premenopausal women generally have higher levels of serum IGF-1 levels compared to postmenopausal women (61-63). Some studies have shown that breast cancer patients in general have higher plasma IGF-1 levels at the time of diagnosis compared to normal (control) subjects (64, 65).

Information looking at the relationship between serum IGF-1, clinical outcome and clinicopathological prognostic factors such as oestrogen receptor status, nodal status, tumour size, and histological grading are lacking. Vadgama et al. measured the serum IGF-1 in breast cancer patients after primary treatment and found that it correlated only to tumour size and progesterone receptor (PR) immunostaining, without any association with age, nodal status, or oestrogen receptor status. His study also showed that patients who received adjuvant Tamoxifen had lower serum IGF-1 levels and this corresponded with a lower probability of recurrent breast cancer and longer overall survival (56, 66). Coskun et al. showed that serum IGF-1 levels were higher in patients with metastases compared with those without or 'normal' controls. There were no differences found between ER+ve and ER-ve metastatic groups or between the non-metastatic and control groups. However, this study involved only a small sample size and cancer cases were not matched to an equal number of controls (67). Holdaway et al. looked at serum IGF-1 levels at baseline and at 1 week post commencement of chemotherapy in patients with early and advanced breast cancer. In this study, there was no significant relationship between basal serum IGF-1 level and survival. Serum IGF-1 levels did not change with chemotherapy in the overall group. Contrary to serum IGFBP-3 levels, the fall in serum IGF-1 also did not seem to have any association with overall survival (58).

Measuring local breast tissue IGF-1 expression seems logical considering that most studies conclude that serum IGF-1 level falls after onset of menopause and would not appear to contribute to late postmenopausal breast cancer leading to the hypothesis that local IGF-1 production may contribute to postmenopausal breast cancer. However, studies correlating local breast tissue IGF-1 expression with clinicopathological feature and prognosis are also limited. Yu et al. showed tissue expression of IGF-1 in 135 tumour tissue cytosols using radioimmunoassay did not show significant correlation between IGF-1 expression with ER, PR, or any other biochemical markers of poor prognosis such as p53, HER-1, HER-2 protein, S-phase fraction or DNA ploidy (59). An earlier study by Mizukami et al. who used immuno-histochemistry also failed to show any correlation between IGF-1 expression, histological features and prognosis but did show a positive correlation between tumour IGF-1 expression and ER content (60). Al-Sarakbi showed that IGF-1 mRNA levels in breast tissue adjacent to breast tumour correlated with the number of metastatic lymph nodes only, but not with any other pathological prognostic factor (61). Toropainen et al. measured IGF-1 expression in tumour and breast stromal tissue using immunohistochemistry in a series of 211 breast cancer cases and showed that IGF-1 immunostaining in tumour areas tended to be higher in cases with axillary lymph node negativity as compared to those with axillary metastasis and also higher in cases with low S-phase fraction compared to higher S-phase fraction. In all cases, patients with positive tumour-IGF-1 staining cases had significantly longer overall survival probability compared to negative tumour-IGF-1 staining cases but no effect on recurrence-free survival. IGF-1 immunostaining intensity in stromal tissue adjacent to breast tumours correlated with tumour size, nuclear pleomorphism, DNA diploidy and increased likelihoods of metastasis at time of diagnosis but did not have any association with recurrence-free survival or overall survival (62). Eppler et al. measured IGF-1 using radioimmunoassay and found that IGF-1 expression was significantly lower in grade 3 tumours compared to grade 1 and 2 tumours. In all histopathological grades, IGF-1 immunoreactivity increased along with ER and PR levels but was inversely related to S-phase fraction. In low grade tumours, tumour IGF-1 levels was associated with longer survival time (63). Overall, most studies suggests that IGF-1 expression is associated with favourable histopathological features and better prognosis. However, more studies are needed to validate these findings.

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