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Development and differentiation of the
mammary gland are dependent on the appropriate temporal expression of both
systemically acting hormones and locally produced growth factors. A large
body of evidence suggests that molecular crosstalk between these hormonal and
growth factor axes is crucial for appropriate cell and tissue function. Two
of the most important trophic factors involved in this process are the
oestrogen (E) and insulin-like growth factor (IGF) molecular axes. The
reciprocal crosstalk that exists between these pathways occurs at
transcriptional/post-transcriptional and translational/post-translational
levels regulate the expression and activity of genes involved in this
process. In a clinical context an important consequence of such crosstalk in
the mammary gland is the role which it may play in the aetiology, maintenance
and development of breast tumours. Although oestradiol (E2) acting
through oestrogen receptors α and β (ERα/β) is important for normal mammary
gland function it can also provide a mitogenic drive to ER + breast
tumours. Therefore over several years anti-oestrogen therapeutic regimens in
the form of selective oestrogen receptor modulators (SERMs — e.g. tamoxifen),
aromatase inhibitors (AI e.g. anastrozole) or selective oestrogen receptor
down regulators (SERDs – e.g. fulvestrant) have been used in an adjuvant
setting to control tumour growth. Although initial response is usually
encouraging, large cohorts of patients eventually develop resistance to these
treatments leading to tumour recurrence and poor prognosis. There are
potentially many routes by which breast cancer (BC) cells could escape
anti-oestrogen based therapeutic strategies and one of the most studied is
the possible growth factor mediated activation of ER(s). Because of this,
growth factor modulation of ER activity has been an intensively studied route
of molecular crosstalk in the mammary gland. The insulin-like growth factors
(IGF-1 and -2) are amongst the most potent mitogens for mammary epithelial
cells and there is accumulating evidence that they interact with the E2
axis to regulate mitogenesis, apoptosis, adhesion, migration and
differentiation of mammary epithelial cells. Such interactions are
bi-directional and E2 has been shown to regulate the expression
and activity of IGF axis genes with the general effect of sensitising breast
epithelial cells to the actions of IGFs and insulin. In this short review we
discuss the evidence for the involvement of crosstalk between the
insulin-like growth factor (IGF) and oestrogen axes in the mammary gland and
comment on the relevance of such studies in the aetiology and treatment of
BC.
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موجز عن المشاركة:
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Oestrogen (E)-dependent breast tumours
can be resistant to anti-oestrogen therapeutic strategies. This may occur by
E-independent activation of oestrogen receptors (ERs) ERα and ERβ by other growth factors. Insulin-like growth factors (IGFs)
are potent mitogens for breast epithelial cells, and evidence suggests that
IGF-I may activate ERα in an E-independent manner to provide a
mitogenic stimulus.
Compelling evidence suggests that ERβ may act as a tumour suppressor to
regulate the activity of ERα,
so it is important to investigate the potential effects of growth factors on
the expression and activity of this ER isoform. Moreover, we have previously
reported that IGFBP-5 inhibits mammary gland function and cell migration, and
stimulates cell adhesion, suggesting that it functions as a tumour
suppressor.
In the present study, we investigated the expression of IGF axis genes and ERα
and β in parental and
tamoxifen-resistant (TamR) MCF-7 cells, using RT-PCR. ERα was expressed at a much higher
level than ERβ in both cell
lines. Furthermore, IGFBP-2, -4 and -5, along with IGF-IR and IGF-2R, were
the most abundantly expressed members of the IGF axis. IGFBP-1,-3 and -6 were
expressed at very low levels. With respect to TamR cells, we found that
IGFBP-5 was down-regulated, while IGFBP-2 was up-regulated. We confirmed
changes in IGFBP-5 and IGFBP-2 expression by using enzyme-linked
immunosorbent assay to measure IGFBP-5 and IGFBP-2 secreted in conditioned
medium. In conclusion, IGFBP-5 and IGFPB-2 emerged as potentially fruitful
novel target proteins with regard to BCa anti-oestrogen therapy.
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