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Jorge R. Pasqualini
BREAST CANCER: PROGNOSIS, TREATMENT AND
PREVENTION (2nd Edition)
Carlo Campagnoli, Patrizia Pasanisi, Clementina Peris and Franco Berrino
Insulin-like Growth Factor-I and Breast Cancer: Epidemiological and
Clinical Data
SUMMARY
Insulin-like growth factor-I (IGF-I) has powerful mitogenic and antiapoptotic effects on many
cell types, including normal and transformed breast epithelial cells. The proliferative effects of
IGF-I on breast cancer (BC) cells are synergistic with those of estrogens.
IGF-I production is present in many tissues and is responsive to Growth Hormone (GH).
Locally produced IGF-I is present also in mammary tissue, particularly in stromal cells clustered
around intra- and interlobular ducts and in adjacent non-neoplastic tissue in case of BC. Despite
the importance of paracrine effects of locally produced IGF-I, also circulating IGF-I could have a
role in stimulating breast tissue and BC cells. This is suggested by several reports proving the
endocrine effects of IGF-I on bone, muscle, and also the breast. Moreover, most epidemiological
studies suggest that circulating IGF-I levels are asociated with breast cancer risk, particularly in
premenopausal women.
Circulating IGF-I is mainly of hepatic derivation . The production of IGF-I by the hepatocites is
stimulated by GH, the secretion of which is influenced by circulating IGF-I level through a
negative feed-back mechanism. In healthy adults, normal levels of IGF-I can range from 100 to
300 ng/ml, and although GH remains the major regulatory factor, there are clearly other
determinants. Among these, nutritional conditions and insulin level have a relevant role, because
they modulate the liver responsivity to GH: fasting and nutrient deprivation cause a decrease in
IGF-I production and serum level Another determinant of serum IGF-I level are genetic factors.
Approximately 99% of IGF-I circulates bound to specific proteins (IGFBPs). The most
important of these proteins is IGFBP-3, which is synthesized in Kupffer cells of the liver under GH
stimulation. More than 75% of circulating IGF-I is carried in a ternary complex composed of IGF-I,
IGFBP-3 and an acid-labile subunit. This ternary complex prevalently acts as a reservoir of IGF-I,
prolonging the half life of IGFs and, possibly, facilitating their endocrine actions.
Insulin enhances GH-stimulated synthesis of IGFBP-3 by increasing levels of GH. Conversely,
insulin inhibits the hepatic synthesis of other IGFBPs, the -1 and –2, that decrease the bioactivity
of IGF-I.
Sex hormones, particularly estrogens, influence the GH/IGF-I axis at various levels. Estrogens
and androgens stimulate GH secretion. However, estrogen can contrast GH action on the liver,
causing a reduction in the synthesis of IGF-I. This is particularly evident in the case of oral
estrogen administration, as a consequence of the supraphysiological concentrations of estrogen
in the liver, due to the hepatic first pass. Oral estrogens of contraceptive pill or of preparations
used as hormone therapy (HT) in menopausal women, cause a decrease in IGF-I level and a
reactive increase in GH level.They also increase IGFBP-1 level, whilst the data on IGFBP-3
modification are not consistent. Transdermal estrogens, at the doses currently used in HT, in
average do not cause variations in IGF-I levels. The effect of oral androgen administration is
opposite to that of estrogens, because they increase IGF-I level. Contrarily to non-androgenic
progestins, that are without effects, androgenic progestins (if orally administered) contrast the
estrogen hepatocellular effect of reducing IGF-I synthesis.
Tibolone, at the currently used dose of 2,5 mg/d, does not modify circulating IGF-I levels.
Some therapies for BC prevention and treatment affect IGF-I level. For instance,
tamoxifen, droloxifene and raloxifene reduce circulating IGF-I and increase.
IGFBP-1 through estrogen agonistic effects on the liver, without causing a reactive increase in
GH secretion. Conversely, specific aromatase inhibitors significantly increase IGF-I level.
A number of new therapeutic approaches, with the aim of reducing IGF-I level and bioactivity
are on study. One approach could be the use of competitive GH receptor antagonist
Pegvisomant. Another strategy points to inhibit IGF activity, ranging from the use of polyethilene
glycol-conjugated IGFBP-1 to the block of IGF receptor (dominant negative IGF-1R, IGF-1R
antisense, IGF-1R antibodies, IGF-1R tyrosine kinase inhibitors). However, anti-IGF-1 and antiIGF-1R therapies raise theoretical concerns for the development of metabolic and cardiovascular
side effects. Actually, epidemiological and clinical data suggest that individuals with low serum
IGF-I have an increased risk of diabetes and vascular problems. Possibly, the best way to
decrease IGF-I level and bioactivity, with the aim of reducing BC risk and BC recurrence, is the
nutritional approach. Actually, with this approach, other metabolic factors of BC are contrasted,
whilst cardiovascular risk is reduced.