Adapted from American Cancer Society 2006 and Hulka et al' 2001'

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(No Transcript)
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Adapted from American Cancer Society (2006) and
Hulka et al. (2001).
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Accurate clinical staging for breast cancer has
always been considered essential before surgery
is undertaken (Sobin Wittekind, 2002). However,
it is important to remember the clinical signs of
breast cancer that would invalidate surgical
attempts at cure. In these instances, initial
referral to a clinical oncologist would be more
relevant.
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The staging systems currently in use are based on
the clinical size and extent of invasion of the
primary tumour (T), the clinical absence or
presence of palpable axillary lymph nodes and
evidence of their local invasion (N), together
with the clinical and imaging evidence of distant
metastases (M). For T13 'a' indicates no
attachment to underlying muscles 'b' indicates
attachment.
Adapted from Sobin Wittekind (2002).
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The TNM classificatio has been subdivided into
four broad categories by the Union Internationale
Contre Cancer. Many expert groups include T2
tumors in stage I.
Adapted from Sobin Wittekind (2002).
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Oestrogen plays an important role in regulating
the growth and differentiation of normal,
premalignant and malignant cell types, especially
breast epithelial cells. The biological effects
of oestrogen are mediated by oestrogen receptors,
which consist of two isoforms (ER-a and ER-ß)
that are transcribed from two genes.AF,
activation function region.
Reproduced with permission from Cui et al. (2005).
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cAMP, cyclic AMP E2, oestrogen 4-OH-E2,
4-hydroxyestradiol ER, oestrogen receptor EGFR,
epidermal growth factor receptor IGF-1,
insulin-like growth factor MAPK, mitogen-actived
protein kinase mRNA, messenger RNA PI3K,
phosphoinositide 3-kinase mtProteins,
mitochrondrial proteins Shc, Src homology 2
domain-containing protein pShc, phosphorylated
Shc protein Ras, GTP-binding protein Raf,
serine/threonine kinase Src, protein tyrosine
kinase. Dashed line arrows indicate putative
pathways.
Reproduced with permission from Yager Davidson
(2006).
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Oestrogens cause activation of various protein
kinases, such as mitogen-activated protein
kinases (MAPK), and increase levels of second
messengers, such as cAMP.EGF, epidermal growth
factor IGF-1, insulin-like growth factor 1
PI3K, phosphoinositide 3-kinase ERK,
extracellular signal-activated protein kinase
JNK, c-jun N-terminal kinase.
Reproduced with permission from Yager Davidson
(2006).
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The progesterone receptor is a nuclear
transcription factor that mediates the biological
actions of its ligand, progesterone. The
progesterone receptor consists of two isoforms
(PR-A and PR-B) that are transcribed from a
single gene using an alternative promoter and
translation start site.AF, activation function
domain.
Reproduced with permission from Cui et al. (2005).
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Growth factor reduction of progesterone receptor
(PR) via direct inhibition of PR gene
transcription and induction of membrane-initiated
oestrogen receptor (ER) signalling.E2,
oestradiol ERK1/2, extracellular regulated
kinase 1/2 HB-EGF, heparin-binding epidermal
growth factor HER, human epidermal growth factor
receptor IGF-IR, insulin-like growth factor-1
receptor mTOR, mammalian target of rapamycin
PI3K, phosphatidylinositol 3-kinase SERM,
selective oestrogen receptor modulator Tam,
tamoxifen.
Reproduced with permission from Cui et al. (2005).
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Binding of epidermal growth factor (EGF) to the
human epidermal growth factor receptor (EGFR)
activates a cellular pathway, with induction of
phosphorylation by intracellular kinases, leading
to nuclear signals that increase cell
proliferation.
Based on Lo et al. (2006).
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Epidermal growth factor receptor (EGFR) family
members are dysregulated in many human cancers,
suggesting a pivotal role in tumorigenesis
(Grünwald Hidalgo, 2003).
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A tumour's hormone receptor status can be
determined by immunohistochemistry. This
photomicrograph demonstrates strong positive
nuclear staining (brown or black) for oestrogen
receptors in an infiltrating ductal carcinoma.
Reproduced with permission from Dietz J et al.
Atlas of Cancer.
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Hormone receptors in breast tissue are measured
semiquantitatively, using simple scoring systems
such as the Allred score or H-score. The Allred
score is a microscopic method conveying the
estimated proportion and intensity of positive
tumour cells (range 08) (Allred et al, 1998).
Reproduced from www.breastcenter.tmc.edu/research/
cores/path/services/er.htm.
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Tumours that express ER and/or PR are deemed to
be endocrine responsive, while those expressing
neither receptor are endocrine unresponsive. ER,
oestrogen receptor PR, progesterone receptor ,
positive (Allred score 2) , negative (Allred
score lt2) ?, unknown. Calculated from the
Nurses' Health Study (2096 incident breast cancer
cases during 1,029,414 person-years of follow-up).
Data from Colditz et al. (2004).
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Endocrine responsiveness is an important
prognostic marker in breast cancer. ER, oestrogen
receptor.
Reproduced with permission from Hess et al.
(2003).
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All patients were treated with systemic endocrine
therapy (tamoxifen in gt90). ER, oestrogen
receptor positive ER, oestrogen receptor
negative PR, progesterone receptor positive
PR, progesterone receptor negative.
Reproduced with permission from Cui et al. (2005).
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Many hormones influence breast development and
function, including oestrogens, progesterone,
androgens, prolactin, and luteinising
hormone-releasing hormone (LHRH). FSH,
follicle-stimulating hormone LH, luteinising
hormone ACTH, adrenocorticotrophic hormone.
Based on Dickson (2000) Russo and Lamarque
(1984).
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The relative risk was calculated with the
low-risk group as the reference group. There is
no association between the risk of breast cancer
and oophorectomy performed at 35 years of age or
older.
Reproduced with permission from Clemons Goss (
2001).
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Oestradiol and, to a lesser degree, other steroid
hormones (e.g., progesterone) drive breast cell
proliferation, which facilitates mutation,
enhances fixation of mutations or facilitates
expression of genetic errors by loss of
heterozygosity by defects in DNA repair. Germline
mutations in relevant tumour-suppressor genes
accelerate the transformation to the malignant
phenotype.
Reproduced with permission from Henderson et al.
(2000).
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ACI denotes a cross between August and
Copenhagen-Irish strains and SENCAR sensitive to
carcinogenesis.
Reproduced with permission from Yager Davidson
(2006).
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Arrows indicate sites of conversion of androgen
to oestrogen.
Reproduced with permission from Clemons Goss (
2001).
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CYP11, 11-hydroxylase CYP17, 17-ßhydroxylase
CYP21, 21-hydroxylase DHEA, dehydroepiandrosteron
e E1, oestrone E2, oestradiol 3ß-HSD,
3ß-hydroxysteroid dehydrogenase 17ß-HSD,
17ß-hydroxysteroid dehydrogenase 17-KSR,
17-ketosteroid reductase P450, cytochrome P450
scc, side-chain-cleavage enzyme.
Reproduced with permission from Clemons Goss
(2001).
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With advancing age there is a progressive
increase in the efficiency with which circulating
androgens are converted to oestrogens. This is
associated with two- to fourfold increases in
both aromatase activity and aromatase mRNA in
adipose tissue from many body sites, including
the buttocks, thighs and abdomen.
Reproduced with permission from Bulun Simpson
(1994).
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Paracrine and autocrine mechanisms establish a
positive feedback loop, leading to the continuing
growth and development of the tumour. cAMP,
cyclic AMP DEX, dexamethasone E2, oestradiol
IL, interleukin LIF, leukaemia inhibitory
factor OSM, oncostatin M PGE2, prostaglandin
E2 TNF-a tumour necrosis factor-alpha.
Reproduced with permission from Simpson (2000).
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Aromatase is the final rate-limiting step in
oestrogen biosynthesis, thus selective blockade
of the cytochrome P450 aromatase enzyme
(P450arom) has no effect on upstream hormones.
17ß-HSD, 17ß-hydroxysteroid dehydrogenase
17-KSR, 17-ketosteroid reductase.
Based on Clemons Goss (2001).
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Aromatase inhibitors are described as first-,
second- and third-generation according to the
chronological order in which they were developed,
and are further classified as type 1 or type 2
according to their mechanism of action.
Reproduced with permission from Smith Dowsett
(2003).
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Reproduced with permission from Smith Dowsett
(2003).
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Adapted from Lake Hudis (2002).
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