1. Introduction
Preinvasive and premalignant lesions of the breast
are defined as ‘precursor lesions’ and represent a group of
extremely heterogeneous lesions that have yet to be clearly
classified. In addition, the risk of the neoplastic evolution of
the lesions is not yet completely known. At present, these lesions
are defined only as ‘risk indicators’ for breast cancer (BC), i.e.
lesions with a variable potential to progress to malignant
phenotypes. BC precursor lesions include atypical ductal
hyperplasia (ADH), atypical lobular hyperplasia (ALH), columnar
cell lesions (CCLs), ductal carcinoma in situ (DCIS), flat
epithelial atypia (FEA), usual ductal hyperplasia (UDH) and lobular
carcinoma in situ (LCIS) (1).
The molecular and morphological features of these
lesions are indicative of a multistep model of breast tumorigenesis
that provides a transition from normal epithelium to invasive
carcinoma (1). Sequential steps
differ according to whether the progenitor cells originate from the
ducts or lobules: Ducts, UDH vs. FEA vs. ADH vs. DCIS vs. IDC
(invasive ductal carcinoma); and lobules, HL vs. ALH vs. LCIS vs.
ILC (invasive lobular carcinoma; Fig.
1) (1).
Consistent with the ‘clonal evolution’ hypothesis,
there are numerous studies that show common genetic alterations
among the precursors of low-grade BC (low-grade DCIS and ADH)
(2).
However, it has also been shown that these lesions
do not have the same probability for progression into invasive
carcinoma (3).
Recently, as a result of the use of specific and
sophisticated technologies, a wide range of molecular alterations
associated with preneoplastic forms have been identified. Although
they represent a ‘risk of evolution’, their real diagnostic and
prognostic value remains unclear.
2. Cytogenetic and molecular alterations in
precursor lesions
Genotypic-phenotypic potential correlations are
consistent with the hypothesis of a multistep evolution of
precursor lesions. Several allelic imbalances have been identified
in CCLs, located at 3p, 9p, 10q, 11q, 16q, 17p and 17q (4). Moreover, a number of copy number
alterations have been described, including the loss of 16q and
chromosome X and the gain of 15q, 16p, 17p and 19q (5). ALH and LCIS have a number of common
cytogenetic abnormalities, in particular, the loss of 16q, 16p and
17p and the gain of 6q (6).
In addition, ADH and DCIS exhibit extremely similar
cytogenetic patterns consistent with the hypothesis of progression.
These cytogenetic abnormalities largely involve the loss of 16q and
17p and the gain of 1q (7). With
regard to alterations in the expression of specific molecular
markers, in certain cases localized in areas that exhibit the
chromosomal aberrations described, the estrogen receptor (ER) must
be considered. Not all precursor lesions show a positivity for ER,
but in the majority of cases, its presence is an important risk
factor, particularly if associated to the Ki67 expression, as in
DCIS (8). By contrast, ERβ
expression is decreased during the supposed precursor lesion
progression steps (9). In addition,
progesterone receptor expression represents a marker of
progression, particularly if associated with ER positivity.
Furthermore, its expression appears to correlate with histological
grade, but not to the prognosis of IDC patients (10).
With regard to HER-2/c-erb2,
hyperexpression/amplification has been detected in ADH and in 25%
of LCIS cases if associated with invasive components (11). In addition, the aberrant expression
of various molecules of the cell cycle, including p21, p27 and p16,
has been identified in BC precursor lesions (12). An additional molecular marker
associated with BC progression is Bcl-2. In particular, its
expression decreases gradually during the steps of BC tumor
evolution and its negativity has been associated with poor
prognosis (13). Moreover, Bcl-2
positivity has been identified to correlate with p53 negativity in
normal breast tissue and several BC precursor lesions (14). Bcl-2 expression is often also
associated with Ki67 expression, in fact, high Ki67 expression,
associated with negativity for Bcl-2, has been reported to
correlate with the development of poorly-differentiated carcinoma.
By contrast, alterations in p53, well described in invasive BCs,
are present in DCIS only (15).
E-cadherin is a molecular marker that is well
characterized in BC precursor lesions, mainly as it is located in
the 16q chromosomal region where losses are commonly described
(16).
Finally, epigenetic modifications have been reported
to be associated with BC precursor lesions, in particular, gene
methylation. E-cadherin hypermethylation has been highlighted in
DCIS and the methylation pattern of this gene is consistent with
the hypothesis that DCIS represents an IDC precursor (17).
3. Conclusions
Molecular techniques, including DNA microarrays,
immunohistochemistry and cytogenetic analysis, have made a
significant contribution, in a number of cases, to the definition
of specific molecular alterations that are common to several
lesions at a ‘high risk’ of evolution (18).
However, cellular models suitable for functional
studies on the molecular alterations identified, are extremely
limited and not representative of the numerous
preinvasive/precursors lesions of BC. Furthermore, in the majority
of cases, the variable molecular signatures of precancerous lesions
are not associated with transformation to the invasive phenotype
(3). Therefore, the specific and
defined molecular steps are not necessarily identified.
Thus, the existence of a multistep process of
evolution of BC precursors lesions remains unknown, preventing the
assignment of valid prognostic value to the molecular alterations
associated.
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