Invasive breast carcinoma - IARC

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Fig. 1.66 Poorly differentiated DCIS. A Immunohistochemical staining and bright field in situ hybridization (BRISH) of cyclin D1 in the same case of DCIS. Strong
staining of poorly differentiated DCIS. B Immunohistochemical staining and BRISH of cyclin D1 in the same case of DCIS. BRISH with a chromosome 11-specific
(peri)centromeric probe. C BRISH with the cyclin D1 specific cosmid. Immunohistochemical staining and BRISH of cyclin D1 in the same case of DCIS. BRISH with
the cyclin D1 specific cosmid. Reprinted with permission from C.B. Vos et al. {3035}.
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o v e re x p ression as a substitute for the
analysis of gene amplification. Amplification
of subregions of 8q can be
complex. There appears to be at least
one additional oncogene mapping to
c h romosome 8q12-22, which has not
been identified yet.
1 0 q 2 6 : The fibroblast growth factor
receptor 2 (FGFR2; formerly: BEK) gene
encodes a cell membrane located
receptor for fibroblast growth factor. This
gene is amplified in approximately 12%
of breast carcinomas {41}.
11q13: Amplification of the cyclin D1
gene (CCND1), encoding a nuclear protein
involved in cell cycle regulation, has
been found in 15-20% of breast tumours,
in association with estrogen re c e p t o r
positivity. Cyclin D1 can also bind to the
estrogen receptor, resulting in ligandindependent
activation of the receptor
{3273}. Immunohistochemically, cyclin
D1 appears to be overexpressed in 80%
of invasive lobular carcinomas, but is not
always accompanied by CCND1 gene
amplification {2133}.
1 7 q 1 2 : The human epidermal gro w t h
factor receptor-2 (ERBB2) proto-oncogene
(also known as HER2, and equivalent
to the rodent neu gene) encodes a
185-kD transmembrane glycopro t e i n
with intrinsic tyrosine kinase activity. A
ligand for ERBB2 has not been identified
but it is hypothesized that ERBB2 amplifies
the signal provided by other receptors
of this family by heterodimerizing
with them. Ligand-dependent activation
of ERBB1, ERBB3, and ERBB4 by EGF or
h e regulin results in hetero d i m e r i z a t i o n
and, thereby, ERBB2 activation. ERBB2
amplification results in overexpression of
ERBB2 protein, but not all tumours with
overexpression have amplified 17q12.
Overexpression is found in approximately
20-30% of human breast carcinomas
{2962}. In breast cancers with normal
E R B B 2 copy number, expression of
ERBB2 may be variable but is very rarely
as high as that in tumours with ERBB2
amplification (usually 10-fold to 100-fold
higher and equivalent to millions of
monomers). Numerous studies have
investigated the relationship between
E R B B 2 status and clinicopathological
characteristics in breast cancer {2962}.
17 q 22 - q 24 : At least three genes
(R P S 6 K B 1, PAT 1, and T B X 2) have been
found to be co-amplified and overe x-
p ressed in ~10% of breast cancers {181}.
F u rther analysis identified R P S 6 K B 1,
M U L, A P P B P 2, T R A P 240
and one
unknown gene to be consistently overe x-
p ressed in two commonly amplified subregions
{1896}. The ribosomal protein S6
kinase (RPS6KB1) is a serine-thre o n i n e
kinase whose activation is thought to re g-
ulate a wide array of cellular pro c e s s e s
involved in the mitogenic re s p o n s e
including protein synthesis, translation of
specific mRNA species, and cell cycle
p ro g ression from G1 to S phase.
20q13: It is presently unknown whether
the CSE1L/CAS gene, the NCOA3 gene
or any other gene in this region serves as
the target for the amplification, which is
found in approximately 15% of breast
carcinomas. Three independent regions
of amplification have been identified
and their co-amplification is common.
Cellular apoptosis susceptibility (CAS)
encodes a protein, which may have a
function in the control of apoptosis and
cell proliferation {346}. N C O A 3 g e n e
encodes a co-activator of the estrogen
receptor {109}, and its amplification has
been found to be associated with estrogen
receptor positivity. High resolution
mapping of the amplified domains has
suggested that a putative oncogene,
ZNF217, and CYP24 (encoding vitamin D
24 hydroxylase), whose overexpression
is likely to lead to abrogation of growth
control mediated by vitamin D, may be
targets for the amplification {60}.
The S T K 1 5 gene (also known as BTA K
and Aurora-A) is amplified in approximately
12% of primary breast tumours,
as well as in breast, ovarian, colon,
p rostate, neuroblastoma, and cervical
cancer cell lines {3259}. S T K 1 5
encodes a centrosome-associated
s e r i n e - t h reonine kinase, and may also
be overe x p ressed in tumours without
amplification of 20q13 {1885}. Centrosomes
appear to maintain genomic stability
through the establishment of bipolar
spindles during cell division, ensuring
equal segregation of re p l i c a t e d
c h romosomes to daughter cells.
D e regulated duplication and distribution
of centrosomes are implicated in chromosome
segregation abnorm a l i t i e s ,
leading to aneuploidy seen in many
cancer cell types. Elevated S T K 1 5
e x p ression induces centrosome amplification
and overrides the checkpoint
mechanism that monitors mitotic spindle
a s s e m b l y, leading to chro m o s o m a l
instability {83,1885,3259}.
Loss of heterozygosity (LOH)
Loss of heterozygosity (LOH) has been
found to affect all chromosome arms
Invasive breast carcinoma
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