Oestrogen/insulin-like growth factor-I receptor interaction in early breast cancer: clinical implications

B. A. Stoll,+

Oncology Department, St Thomas’ Hospital, London SE1 7EH, UK

Received 12 June 2001; revised 12 September 2001; accepted 25 September 2001.


    Abstract
 Top
 Abstract
 Introduction
 Postulated role for abnormal...
 Postulated role for ER/IGF-IR...
 Role of obesity in...
 Clinical implications
 Conclusion
 References
 
The expression of oestrogen receptor (ER) and that of the insulin-like growth factor-I receptor (IGF-IR) are positively correlated in breast cancer specimens. Their function is strongly linked in enhancing proliferative activity in normal and malignant human mammary epithelial cells in culture. This review examines the likely role of such a mechanism in the increased breast cancer risk reported in postmenopausal women with abdominal obesity.

Precancerous breast lesions show an increased proportion of ER-positive cells with high proliferative activity, and recent studies suggest that genetic mutations or epigenetic variants in the ER alpha gene may increase the ER’s sensitivity to oestrogen stimulation. Abdominal obesity in women is associated with higher concentrations both of free oestradiol and free IGF-I. Activation of their respective receptors may induce synergistic stimulation of mammary carcinogenesis. However, there is clinical evidence that progression in precancerous breast lesions may be delayed or reversed. Involution occurs spontaneously in a proportion of duct carcinoma in situ (DCIS) (intraductal) lesions as women approach the menopause, and antioestrogen therapy has been shown to reduce recurrence and progression of DCIS lesions.

Conclusions

Intervention trials in breast cancer prevention would greatly benefit from surrogate response markers which could predict long-term benefit. Changes in ER and IGF-IR expression apart from those in standardised cytomorphological criteria, might predict the likelihood of DCIS involution in cancer prevention trials. Future studies could involve examination of serial core biopsies from normal breast tissue during trials of antioestrogens, retinoids or weight-reduction interventions. Correlation of changes in these markers with changes in circulating IGF-I and oestradiol concentrations may help to clarify the roles of the markers.

Key words: abdominal obesity, breast cancer, duct carcinoma in situ, insulin-like growth factor-I, oestrogen receptor {alpha}, surrogate response biomarker


    Introduction
 Top
 Abstract
 Introduction
 Postulated role for abnormal...
 Postulated role for ER/IGF-IR...
 Role of obesity in...
 Clinical implications
 Conclusion
 References
 
Oestrogen clearly enhances proliferative activity in mammary epithelial cells although the molecular mechanisms are uncertain. One major pathway is likely to be mediated by the oestrogen receptor (ER) and others may involve a variety of oestrogen metabolites capable of causing DNA mutations [1]. ER-mediated pathways are clearly involved both in normal and malignant growth of mammary epithelial cells. However, whilst serum concentrations of oestradiol have been shown to be higher both in pre- and postmenopausal breast cancer cases [2], correlation between oestradiol concentrations and tumour ER expression is uncertain [35].

Oestrogen receptor-mediated response to oestrogen in mammary cells is modulated by multiple nuclear factors including co-activators, co-repressors and integrator proteins [6]. They can lead to genomic instability and influence cell cycle progression and apoptosis. Pathological studies have shown that progression of mammary carcinogenesis is usually associated with evidence of ER dysregulation which involves increase in the number and proliferative activity of ER-positive epithelial cells [7]. The odds of finding breast cancer are reported to be 6.5-fold higher in mastectomy specimens with an ER-positive epithelium of this type than in those with an ER-negative epithelium [8].

Cohort studies have also shown that higher circulating concentrations of insulin-like growth factor-I (IGF-I) are associated with an increased risk of premenopausal breast cancer [9]. The risk of duct carcinoma in situ (DCIS) in premenopausal women is also increased with higher IGF-I concentrations [10]. In breast cancer specimens, expression of the IGF-I receptor (IGF-IR) is positively correlated with that of ER [11], and in the laboratory, cross-talk has been shown between the IGF-IR and ER signalling pathways in stimulating proliferation in normal and malignant human mammary epithelial cells [12–15].

Supporting the hypothesis of a link between ER and IGF-IR in the promotion of human mammary carcinogenesis is evidence from multiple prospective studies, confirming a positive association between abdominal obesity and increased breast cancer risk in postmenopausal women [16–19]. Obesity in women increases free oestrogen concentrations [20] and may stimulate proliferative activity in mammary epithelium through ER-mediated pathways. Obesity is also associated with increased free IGF-I concentrations [21] and this is likely to up-regulate expression of IGF-IR.

There are inconsistencies in the reported association between breast cancer risk in obese postmenopausal women and their serum oestrogen concentrations [22], and the lowered survival rate associated with obesity in postmenopausal women with breast cancer is independent of the tumour ER status [23]. The review examines experimental and clinical evidence that abnormal ER expression and up-regulation of IGF-IR expression in human mammary epithelium may act synergistically in enhancing promotion of carcinogenesis.


    Postulated role for abnormal ER expression
 Top
 Abstract
 Introduction
 Postulated role for abnormal...
 Postulated role for ER/IGF-IR...
 Role of obesity in...
 Clinical implications
 Conclusion
 References
 
In the normal premenopausal breast, ER-positive cells are sparse but their numbers increase with age, reaching a plateau after the menopause. The proportion of ER-positive cells is only slightly increased in hyperplastic lesions without atypia, but grossly increased in atypical ductal hyperplasia and DCIS, even in the case of young women [7]. In these precancerous lesions, the ER-positive cells also show an abnormal increase in proliferative activity [24].

An increased proportion of ER-positive epithelial cells showing proliferation has been proposed to mark precancerous change in the breast [7, 8, 12, 24]. It may result from either genetic or epigenetic damage and may involve chromosomal rearrangement or exon deletions [25]. Major chromosomal changes have not so far been reported in the ER gene of breast cancer cells but splice variants are described in which one or more exons are missing from the RNA [26].

Variants in the ER gene may also explain paradoxical observations on the association between tumour ER expression and breast cancer prognosis after primary treatment. Although higher ER expression is widely assumed to predict a longer recurrence free period and survival, there is also evidence to the contrary [2730].

Multiple studies have distinguished the ER alpha subtype from ER beta in normal, precancerous and cancerous epithelium of the breast. The majority of breast cancers express both types of protein but a higher ER alpha/ER beta ratio is associated with highly proliferative and poorly differentiated tumours. In the case of DCIS also, decreased ER beta expression is found in lesions with high proliferative activity [31]. The association of higher levels of the ER alpha subtype with increased proliferative activity both in breast cancer and DCIS suggests that it may enhance the progression of carcinogenesis [32].

As noted above, such progression may involve either a genetic mutation or an epigenetic change regulated by the cell environment. A somatic mutation has been reported in the ER alpha gene in a proportion of epithelial hyperplasia lesions in the breast [33]. Increased proliferation was observed in the cells following subphysiological concentrations of oestrogen and it was suggested that hypersensitisation to oestrogen stimulation might accelerate progression towards invasive breast cancer. Other studies have reported epigenetic changes, associated with DNA methylation in the promoter regions of ER alpha genes, to be negatively associated with ER alpha expression in breast cancer specimens [25]. The observation may suggest that they have a role in loss of ER expression and progression to autonomy [34].

Clinical observations suggest that whether such progression results from genetic mutation or epigenetic changes, the progression of DCIS to invasive cancer is not inevitable. The genes may revert to normal function even if only for a limited period [35]. Thus, administration of the antioestrogen tamoxifen has been shown to reduce progression of DCIS lesions by 30–40% in pre- and postmenopausal women [36]. Moreover, mammographic and pathological studies show that the frequency of DCIS falls sharply after the age of 40 years [3740] and that there is a lowered age-specific incidence of DCIS in the 40–49 years age group [41]. This occurs at a time of falling oestrogen production in the ovaries and many of the abnormal ER-positive cells in DCIS lesions show expression of cyclins which are known to be under oestrogen control [7].


    Postulated role for ER/IGF-IR interaction
 Top
 Abstract
 Introduction
 Postulated role for abnormal...
 Postulated role for ER/IGF-IR...
 Role of obesity in...
 Clinical implications
 Conclusion
 References
 
Breast cancer specimens show greater expression of IGF-IR than do benign tumours or normal mammary epithelial tissue [4244]. Expression of IGF-IR in such specimens is positively correlated with tumour ER expression [11]. In culture, both normal and malignant human mammary epithelial cells show interaction between ER and IGF-IR in enhancing proliferative activity [1215]. Although IGF-I alone stimulates proliferation in ER-positive breast cancer cells in culture, the effect is enhanced by the addition of oestradiol, whilst increased IGF-I activity stimulates ER expression [45].

A synergistic effect has also been shown in normal breast epithelial tissue in vivo from combined stimulation by IGF-IR and oestradiol [12]. Oestradiol administration to athymic mice carrying xenografts of normal human mammary epithelium causes up-regulation of IGF-IR expression and enhanced proliferative activity. The observation suggests that the combined effect of oestradiol and IGF-I on cell growth might enhance the risk of developing breast cancer.

Such a response is likely to be mediated through the insulin receptor signalling substrate (IRS-1) and this has been shown both in culture [13] and also in xenografts of human breast cancer cells in athymic mice [46]. It should however be noted that the role of IGF-I in the progression of established breast cancer is still not clear and that IGF-IR expression is decreased in aggressive breast cancers [15]. The positive correlation between ER/IGF-IR expression and proliferative activity is lost when hormonal autonomy appears and the expression of IGF-IR and IRS-1 in breast cancer specimens is then inversely associated with the proliferative activity of the tumour [47].

Observations on the molecular effect of antioestrogens on breast cancer are relevant. The antioestrogen tamoxifen inhibits proliferative activity of human breast cancer cells in culture and has been shown to interfere with IGF-IR expression and its signalling through the IRS-1 pathway [15]. However, other mechanisms may also be involved. Thus, xenografts of ER-positive human breast cancer cells into athymic mice receiving tamoxifen supplements showed no interference with progression to invasive cancer although evidence of precursor lesions was considerably reduced [48]. Again, xenografts of ER-positive human DCIS lesions into athymic mice receiving Faslodex (a pure antioestrogen) showed a higher degree of apoptosis in the graft but no inhibition of its proliferative activity [49].


    Role of obesity in breast cancer risk
 Top
 Abstract
 Introduction
 Postulated role for abnormal...
 Postulated role for ER/IGF-IR...
 Role of obesity in...
 Clinical implications
 Conclusion
 References
 
Multiple cohort studies confirm that abdominal fat accumulation is associated with a greater risk of postmenopausal breast cancer than is peripheral distribution of obesity [1619]. Abdominal obesity is associated with increased adrenocortical production of androgens, and androstenedione is then aromatised to oestrogen in fat deposits [50]. Free oestradiol levels are increased also by diminished hepatic production of sex hormone-binding globulin in obesity [51].

Although abdominal obesity is generally associated with low circulating concentrations of total IGF-I [52], recent studies have shown that the free IGF-I concentrations are higher in obese than in normal subjects [21, 53]. The higher levels of free IGF-I are likely to result from chronically depressed levels of IGF-I binding proteins which are associated with the presence of hyperinsulinaemia [54]. Free IGF-I is thought to offer a better measure of its bioactivity than is total IGF-I [55], and a recent study reports higher free IGF-I to be associated with increased risk of breast cancer in women [56].

Increased free oestrogen concentrations acting through ER or other pathways are likely to be a major factor in the increased breast cancer risk related to abdominal obesity in postmenopausal women [19]. Increased tumour ER expression has recently been associated with obesity in postmenopausal breast cancer [57, 58], although older studies reported conflicting findings [50, 59]. A fall is seen in the proportion of ER-positive tumours in the years leading up to the menopause [60]. In the case of obese women, the last menstrual period occurs most commonly between 50 and 55 years of age but in the case of lean women, it is more commonly between 45 and 50 years of age [61].

It is still uncertain to what extent the presence of obesity contributes to breast cancer risk by mechanisms other than by increasing free oestrogen concentrations and up-regulating tumour ER expression. As noted above, a higher body mass index in postmenopausal women is likely to increase the odds of an ER-positive tumour but this is not confirmed in premenopausal women [5, 57]. On the other hand, it has been reported that abdominal obesity is associated with increased odds of ER-positive tumours in premenopausal women [50, 58]. A recent study in Japanese women shows that IGF-IR expression is increased in breast cancer tissue compared to normal breast tissue in obese postmenopausal women but not in obese premenopausal women [62].

Ethnic factors influence predisposition to abdominal obesity, and its prevalence may influence a population’s breast cancer incidence. Both obesity and breast cancer are relatively less common in Japanese women than in Caucasian women, and this applies particularly to postmenopausal breast cancer [63]. A recent study reports that healthy Japanese postmenopausal women are showing increasing evidence of hyperinsulinaemic insulin resistance and an associated increase in body mass index [64]. Again, obesity in postmenopausal Japanese breast cancer patients is associated with increased tumour ER positivity, as it is in Caucasian women [65]. As noted above, it is also associated with increased IGF-IR expression in the tumour [62].


    Clinical implications
 Top
 Abstract
 Introduction
 Postulated role for abnormal...
 Postulated role for ER/IGF-IR...
 Role of obesity in...
 Clinical implications
 Conclusion
 References
 
Experimental and clinical evidence suggest that progression of DCIS to invasive breast cancer may be enhanced by genetic or epigenetic change in the ER alpha gene, but that such a progression may be delayed or reversed. Regression of DCIS lesions has been shown to occur spontaneously and recent clinical trials show promising results from treatment by the antioestrogen tamoxifen or the retinoid fenretinide. In a randomised trial of DCIS cases, tamoxifen added to a combin-ation of lumpectomy and radiotherapy caused a 31% reduction in the risk of DCIS recurrence [36]. The subsequent risk of invasive cancer was reduced by 43% and the risk of contralateral breast cancer by about 40%. Pre- and postmenopausal patients were shown to benefit equally.

An intervention study aiming to reduce progression of breast cancer precursor lesions can be used to test surrogate response biomarkers in serial tissue sampling. Evidence of response after a relatively short trial of an intervention might predict subsequent clinical evidence of delayed cancer progression. Stereotactically-guided core biopsies might ensure that the same area of the breast is sampled before and after the preventive intervention [66]. A prospective study is under way at the M.D. Anderson Center [67, 68] examining the effect of tamoxifen and fenretinide on DCIS lesions when given for 2 to 4 weeks in the interval between diagnostic core biopsy and definitive surgery. It is intended to compare effects on cytopathological markers with those of biological markers such as ER and indices of proliferative activity.

It may be useful to summarise the evidence that a change in ER and IGFI-R expression together with a change in the classical cytomorphological criteria might predict the likelihood of DCIS involution in an intervention trial.

Markers of increased breast cancer risk in women include raised oestradiol and IGF-I concentrations in the serum, and dysregulated ER expression and up-regulated IGF-IR expression in breast epithelial tissue.
Evidence of dysregulated ER activity increases with progression of cancer precursor lesions in the breast. The change may be associated with mutations in the ER alpha gene or with epigenetic variants in the promoter region of the ER alpha gene. ER alpha and ER beta genes show different responsiveness to the various selective oestrogen receptor modulators (SERMs). Identification of variants in ER genes may lead to more selective use of SERMs [69].
Obesity in women, particularly if predominantly abdominal in distribution, is associated with high concentrations of both free IGF-I and free oestradiol. Obesity is associated with increased risk of DCIS lesions in women under 45 years of age and also with an increased risk of DCIS recurrence after lumpectomy. Weight reduction may reduce this risk and there is evidence that DCIS progression may also be reduced by the administration of tamoxifen or fenretinide. It is relevant that administration of the agents is associated in both cases with a reduction in circulating IGF-I concentrations.
Evidence of dysregulated ER expression, change in the ER alpha/ER beta ratio and up-regulated IGF-IR expression in such trials might be compared with signs of classical cytomorphological markers of progression in carcinogenesis. Obese women at increased risk of breast cancer might be included in such intervention trials, which could at the same time test the usefulness of the biological markers as surrogate response markers.


    Conclusion
 Top
 Abstract
 Introduction
 Postulated role for abnormal...
 Postulated role for ER/IGF-IR...
 Role of obesity in...
 Clinical implications
 Conclusion
 References
 
Intervention studies of tamoxifen, fenretinide or weight reduction might examine changes in the expression of ER and IGF-IR in breast ductal epithelium as surrogate markers of DCIS involution. Additional studies of changes in circulating IGF-I and oestradiol concentrations might help to clarify observed differences in the metabolic/endocrine factors which promote mammary carcinogenesis in the different age groups, and the relative influence of abdominal and peripheral fat accumulation.


    Footnotes
 
+ Correspondence to: Fax: +44-020-7928-9968. Back


    References
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 Abstract
 Introduction
 Postulated role for abnormal...
 Postulated role for ER/IGF-IR...
 Role of obesity in...
 Clinical implications
 Conclusion
 References
 
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