Open Journal of Pathology, 2013, 3, 174-179
Published Online October 2013 (
Copyright © 2013 SciRes. OJPathology
Study of the Expression of ALDH1 and CD44 Stem Cell
Markers in Male Breast Cancers
Ping Gong1*, Bruce Boman2, Juan Palazzo1
1Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University Hospital, Philadelphia, USA; 2Cancer Genetics
and Stem Cell Biology, Helen F. Graham Cancer Center, Christiana Care Health Services, Newark, USA.
Email: *
Received June 19th, 2013; revised July 19th, 2013; accepted July 29th, 2013
Copyright © 2013 Ping Gong et al. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Aims: Male breast cancer represents <1% of all breast cancers. Cancer stem cell (CSC)s have been associated with tu-
mor aggressiveness and drug resistance. CSCs are characterized by CD44 and/or ALDH1 expression. In this study, we
investigated their expression in male breast cancer. Method: Two in situ ductal carcinoma (DCIS) and 18 invasive duc-
tal carcinoma (IDC) male breast cancer cases were studied with Jefferson IRB approval. Membrane staining of CD44
was scored by the percentage of positivity. Cytoplasmic expression of ALDH1 was considered positive. Results: Ten
cases had high CD44 expression, which were all IDC. Both DCIS and in situ component of IDC were CD44 low.
ALDH1 was only positive in 15 IDCs. ALDH1+ cells were mostly in the invasive component. Both DCIS cases were
negative for ALDH1. Among the 15 ALDH1+ IDCs, five with only invasive component had a higher percentage (aver-
age 4.4%) of positive cells compared to the other eight with in situ components (average 2.0%). Metastatic cells in sen-
tinel lymph nodes had a similar expression pattern of CD44 and ALDH1 as their primary tumor. Conclusion: CD44
and ALDH1 are expressed in male breast cancers and they are overexpressed in invasive cancer compared to carcinoma
in situ. These findings suggest that CSCs play an important role in the progression to invasive carcinoma.
Keywords: Male Breast Cancer; Cancer Stem Cell; CD44; ALDH1
1. Introduction
Male breast cancer is a rare disease that represents <1%
of all breast cancer diagnoses [1]. However, the mortality
is 31%, which is considerably higher than for breast
cancer in women [2]. Male breast cancer is usually de-
tected at a more advanced stage than female breast can-
cer [3].
Male breast cancer is biologically different from fe-
male breast cancer. Pathologically, the vast majority of
male breast cancers are invasive ductal carcinomas (IDCs)
[4]. The lobular histotype accounts for only 1.5% of in-
vasive carcinoma. Also, a higher percentage of male
breast carcinomas than female breast carcinomas are es-
trogen receptor and progesterone receptor positive [5].
The HER2/neu allele is less likely to be present in male
breast cancers [6].
More recently, cancer stem cells (CSCs) have been
implicated in the development of solid tumors including
breast cancers [7]. Moreover, CSCs, which have the abil-
ity to both self renew and give rise to differentiated
progeny, have been implicated in the mechanisms of
cancer resistance to chemotherapy and radiation [7]. The
status of CSCs in tumors has therefore become of keen
interest. Therefore, development of markers for SCs and
CSCs has gained increased attention.
Previous studies suggest that stem cell-like popula-
tions in normal female breast tissue are characterized by
the expression of aldehyde dehydrogenase 1 (ALDH1).
ALDH1, an enzyme responsible for oxidation of retinol
to retinoic acid, is important for normal development and
homoeostasis in several organs and is crucial during em-
bryogenesis [8,9]. Breast cancer stem cells also express
ALDH1 and breast CSCs have been isolated on the basis
of increased ALDH1 [10]. Indeed, expression of ALDH1
by breast tissue is considered to be a marker, in breast,
for both normal and malignant stem and progenitor cells.
This finding appears to be clinically important as
ALDH1 expression has been associated with poor clini-
cal outcome and resistance to chemotherapy in female
breast cancers [10].
*Corresponding author.
Study of the Expression of ALDH1 and CD44 Stem Cell Markers in Male Breast Cancers 175
Breast cancer cells with a CD44+/CD24 phenotype
have also been suggested to have tumor-initiating prop-
erties with stem cell-like features and have been shown
to be associated with basal-like cancers and BRCA1 he-
reditary breast cancers in women [11]. The recent study
showed increased invasion and tumorigenicity capacity
of CD44+/CD24 breast cancer MCF7 cells in vitro and
in nude mice [12]. A partial overlap between the CD44+/
CD24/low population and the ALDH1+ population has
been reported. The combined CD44+/ALDH1+ pheno-
type shows an especially high tumorigenic capacity, be-
ing able to form tumors in nude mice from as few as 20
transplanted cells [10]. In this study, we are going to use
CD44 and ALDH1 as cancer stem cell marker.
The tumor microenvironment also affects cancer de-
velopment and plays a significant role in prognosis. This
appears to be true for the effect of stem/progenitor cells
on the prognosis of human breast tumors. Stromal cells
of breast tumors have been shown to be positive for
ALDH1 [13].
Several studies have investigated the correlation be-
tween the expression of CSC markers and prognosis and
drug resistance in female breast cancer. However, the
expression of CSC markers in male breast cancer has not
been well studied. Accordingly, in this study, we ana-
lyzed the expression of two CSC markers—ALDH1 and
CD44—in 19 male breast cancers.
2. Materials and Methods
Approval of the study protocol was obtained from the
Jefferson Internal Review Board. All the male breast
cancers were obtained from the files of the Department
of Pathology of Thomas Jefferson University Hospital
diagnosed between 1982 and 2012. A total of 20 cases
were reviewed to confirm the diagnosis and to pathol-
ogically characterize each tumor. The following informa-
tion was obtained in each case: patient age, tumor sub-
type, size, nuclear and histological grade, and ER and PR
status. The 20 cases included 2 ductal carcinomas in situ
(DCISs) and 18 invasive ductal carcinomas (IDCs).
Immunohistochemical staining was done using forma-
lin-fixed, paraffin-embedded 4 μm sections. Representa-
tive sections were stained with antibodies against both
CD44 (Clone 156-3C11, 1:800 dilution, Thermo Scien-
tific, Fremont, CA) and ALDH1 (1:100 dilution, BD Bio-
science, San Jose, CA]. Staining procedures followed
previously published protocols [13-15]. Specificity of
staining was confirmed by positive controls (liver for
ALDH1 and tonsil for CD44) and negative controls (re-
placement of the primary antibody by PBS).
CD44 staining was detected mainly on the cell mem-
brane and was scored by the percentage of tumor cells
that were positive for the stain (0%, 0% positive tumor
cells; 1%, 1% to 10% positive cells; 2%, 11% to 50%
positive cells; 3%, 51% to 75% positive cells; 4%, 76%
to 100% positive cells) [16]. Tumors with scores 1 and 2
were defined as tumors with low CD44 expression and
tumors with scores 3 and 4 were defined as having high
CD44 expression. The percentage of cells exhibiting cy-
toplasmic expression of ALDH1 in tumor cells was re-
corded. Since no consensus exists for ALDH1 scoring
based on the percentage of cells, any tumor cell with de-
tectable staining according to previous studies [13-15]
was considered positive. We also recorded the percent-
age of tumor cells that were positive.
We also analyzed the cytoplasmic expression of
ALDH1 in stromal cells. The presence of >5% ALDH1
positive cells in the stroma was defined as high expres-
3. Results
Two of the 20 cases (10%) were pure in situ ductal car-
cinomas, whereas the other 18 cases (90%) were invasive
ductal carcinomas with or without an in situ component.
Table 1 lists the following information of the 20 patients:
the diagnosis, age, tumor size, nuclear grade, histologic
grade, the percentage of CD44 positive and ALDH1
positive tumor cells, ALDH1 staining in tumor stroma,
ALDH1 staining score, lymph node metastasis, and ER
and PR expression. Tumor size ranged from 0.7 to 6.0
Ten of 20 cases (50%) had high CD44 expression
(70% - 100% CD44+ cells in tumors), which were all
IDCs (Figure 1). Both DCIS cases had low CD44 ex-
pression (30% - 40% of tumor cells were positive) (Fig-
ure 2). Of the 18 IDC cases, 13 cases also had an in situ
component (Table 2). Interestingly, 11 of 13 (84.6%) of
the in situ components in the invasive cases had low
CD44 expression. Only two cases showed increased
CD44 expression in the in situ components of the tumor.
However, among the invasive components of the 18 IDC
cases, 11 showed high CD 44 expression. Overall, CD44
expression was low in DCIS and in the in situ component
of IDCs; IDCs tended to have higher CD44 expression
than DCISs, especially in the invasive component.
ALDH1 expression in tumor cells showed wide varia-
tion among our cases, ranging from negative to a low
level (1% - 5%) to a high level (5% - 10%). ALDH1 ex-
pression in tumors was positive in 15 of 20 (75%) cases,
all of which were IDCs (Table 3). Both DCIS cases were
negative for ALDH1 expression (Figure 3). Fifteen of 18
(83.3%) IDCs were positive for ALDH1 (Figure 4). Among
the 15 ALDH1+ IDC cases, five had only an invasive
component and nine had both invasive and in situ com-
ponents. Only two cases were positive for ALDH1 ex-
pression in their in situ component. The other 12 cases
were positive for ALDH1 expression in the invasive
component. The five IDC cath only an invasive ses wi
Copyright © 2013 SciRes. OJPathology
Study of the Expression of ALDH1 and CD44 Stem Cell Markers in Male Breast Cancers
Copyright © 2013 SciRes. OJPathology
Table 1. Pathological and immunohistochemical features of all male breast cancers in the study.
Number DX Age Size Ng Hg CD44 ALDH1/TumorALDH1/StromaLN metALDH1 ER PR
1 IDC 89 n/a II III >90 0 low 2/19 0 n/a n/a
2 IDC 86 6 cm III III >90 1 low 1 + +
3 IDC 83 2.5 cm II III 10% - 20%5 high 1 70% - 80% <10%
4 IDC 79 2.5 cm II II 25 3% high 1 0% 90%
5 IDC 69 2 cm III II 30 3% low 4/7 1 90% 5%
6 DCIS 45 0.7 cm III n/a 40 0 high 0 70% - 90% 70% - 90%
7 IDC 67 1.1 cm II II 90 1 high 1 90% 75%
8 IDC 72 1.0 cm II II 100 5% high 1 90% 85%
9 IDC 76 0.7 cm II II 80 0 high 0 70% 60%
10 DCIS 57 3 cm I n/a 30 0 low 1/21 0 100% 100%
11 IDC 79 3 cm II II 100 1 high 1 n/a n/a
12 IDC 67 0.7 cm
II II 70 5% low 1 negative negative
13 IDC 92 n/a III III 20 1 high 1 n/a n/a
14 IDC 105 n/a 20 0 low 0 n/a n/a
15 IDC 63 0.7 cm II I 90 10% high 1 100% 90%
16 IDC 56 2cm II II 95 5% high 1 90% 85%
17 IDC 79 n/a 10 0 low 1 n/a n/a
18 IDC 83 n/a I II 100 1% high 1 90 90
19 IDC 73 1.3 cm II III >90 2% High 0/5 1 90% 90%
20 IDC 69 0.8 cm II I 10 1% Low 1 93% 96%
DCIS = ductal carcinoma in situ; IDC = invasive ductal carcinoma; DX = diagnosis.
Table 2. CD44 expression in different subtypes of male
breast cancer.
CD44 expression
High Low Total
DCIS 0 2 2
IDC 11 7 18
Invasive component 11 7 18
In situ component 2 11 13
Figure 1. Invasive ductal carcinoma with low (A) and high
(B) CD44 expression (Immunohistochemical stain, original
magnification ×200).
Table 3. ALDH1 expression in the tumor and stroma of
different subtypes of male breast cancer.
ALDH tumor
expression ALDH stromal expression
Positive NegativeLow High
DCIS 0 2 1 1
IDC 15 3 7 11
Invasive only 5 0
In situ and invasive
component 10 3
Total 15 5 8 12
Figure 2. Ductal carcinoma in situ with low CD44 expres-
sion (Immunohistochemical stain, original magnification
Study of the Expression of ALDH1 and CD44 Stem Cell Markers in Male Breast Cancers 177
Figure 3. Ductal carcinoma in situ with negative ALDH1
expression (Immunohistochem ical stain, original magnifica-
tion ×200).
Figure 4. Invasive ductal carcinomas with negative (A) and
positive (B) ALDH1 expression (Immunohistochemical stain,
original magnification ×200).
component had a higher percentage (1% - 10%, average
4.4%) of ALDH1 positive cells in their tumors compared
to the other ten ALDH1+ IDC cases with in situ compo-
nents (1% - 5%, average 2.0%). ALDH1+ CSCs were
present in IDCs, especially the invasive component, but
were absent in DCIS. ALDH1 expression was higher in
IDCs that have only an invasive component compared to
IDCs with an in situ component.
Three cases had sentinel lymph node metastases at the
time of surgery. We were able to perform the staining in
only one of the positive lymph nodes (case #1). These
metastatic cells had similar expression patterns of CD44
and ALDH1 compared to the primary tumor: high CD44
expression and negative ALDH1 expression. The other
two cases with metastases in the lymph nodes showed
variable ALDH1 staining and low CD44 expression in
the primary tumors.
We also found that stromal cells in the region of the
tumors and within the tumors were positive for ALDH1.
Eight cases had low ALDH1 stromal expression, while
the other 12 cases had high stromal expression, of which
11 were IDCs, and 1 was a DCIS. Stromal expression of
ALDH1 in male breast cancer did not show any correla-
tion with prognosis.
4. Discussion
Stem cell (SCs) is cells that have the ability to perpetuate
themselves through self-renewal and to generate mature
cells of a particular tissue through differentiation [7].
Cancer stem cells (CSCs), akin to normal stem cells, are
postulated to have the ability to self renew and give rise
to differentiated progeny. It has been shown that solid
cancers are comprised of a heterogeneous population of
cells that differ in morphology, marker expression, pro-
liferation capacity, and tumorigenicity [7,17]. Two gen-
eral models of heterogeneity are proposed: 1) cancer
cells of many different phenotypes have the potential to
proliferate extensively, but any one cell would have a
low probability of exhibiting this potential in an assay of
clonogenicity or tumorigenicity; 2) Most cancer cells
have only limited proliferative potential, but a subset of
cancer cells (i.e. CSCs) consistently proliferate exten-
sively in clonogenic assays and can form new tumors
when transplanted. The CSC concept provides an expla-
nation for the limitations of current cancer treatment—it
is designed to target rapidly dividing cells, not the rela-
tively quiescent CSCs. If we could better understand how
CSCs drive tumor growth, we could develop ways to
target CSCs, which would suggest new strategies for
cancer prevention and therapy [7,17,18].
Progress in the field of SC biology has been long ham-
pered by difficulties in identifying, isolating, and charac-
terizing SCs until SC markers were identified. The CSCs
and the tumors they form demonstrate the capacity for
serial passage in immunocompromised mice and for dif-
ferentiation into multiple cell lineages resembling the
original tumor [18-20]. For example, CSCs isolated using
ALDH1+/CD44+/CD24– markers from breast cancers
were able to generate tumors in immunocompromised
mice with as few as 20 cells [10]. In addition to the stud-
ies of CSCs in breast tissue, ALDH1+ CSCs have also
been shown to contribute to colon tumorigenesis [21].
Since ALDH1 and CD44 have been well established as
cancer stem cell markers in breast cancer, we are using
these two markers to study the role of cancer stem cell in
male breast cancer.
CSCs are thought to play a role not only in initiation
but also progression and recurrence of cancer. CSC stud-
ies of female breast cancers have shown that expression
of SC markers is associated with aggressive phenotypes
such as high histologic grade, the absence of ER or PR
positivity, and HER2 overexpression [22]. CSCs are also
increased in metastatic sites [23].
Little is known about CSCs in male breast cancer be-
cause it is an uncommon disease and not frequently
studied. We found that in male breast cancers, ALDH1 is
positive in IDCs but not DCISs. CD44 expression is low
in DCISs and in the in situ component of IDCs, but high
in the invasive components of IDCs. Lymph node me-
tastases appeared to show a similar expression pattern
Copyright © 2013 SciRes. OJPathology
Study of the Expression of ALDH1 and CD44 Stem Cell Markers in Male Breast Cancers
compared to their primary tumors.
The fact that positivity for CD44 and ALDH1 tended
to be low in DCISs and high in IDCs suggests that CSCs
become overpopulated during the progression to invasive
cancer. Our findings on expression of CSC markers in
male breast cancers are similar to those known for female
breast cancers [10]. Given that CSC overpopulation may
be responsible for progression to invasive male breast
cancer; this suggests that CSCs are prime targets for anti-
cancer therapy. This view is consonant with ideas on new
treatment approaches for female breast cancers [18,21].
Male and female breast cancers differ in histological
subtype [3]. There are also differences at the molecular
level. In our previous studies, we found that, compared to
female breast cancers, male breast cancers have a spe-
cific miRNA expression signature [17] with significantly
dysregulated miRNA: 4 overexpressed and 13 underex-
pressed) [24]. The targets of these miRNA genes include
HOXD10 and VEGF, which may be directly involved in
male breast cancer development [24]. Additionally, the
cytokeratin profiles of male breast cancer demonstrate
that male breast cancers have a similar frequency of
basal-like phenotype to that of female breast cancers. The
expression of CK5/6 and CK14 identifies a subset of
pathologically aggressive male breast cancers [25].
ALDH1 expression is found not only in breast carci-
noma cells, but also, has been detected in stromal cells.
Stromal expression of ALDH1 in female breast cancer
was predictive of disease-free survival in triple negative
tumors [13]. This would indicate that the tumor microen-
vironment might play a role in determining the prognos-
tic impact of cancer stem cells. However, male breast
cancers are usually not triple negative tumors. We only
had 3 cases with metastasis to the lymph nodes, and there
were not any differences in ALDH1 expression between
stromal and epithelial tumor tissues compared to cases
without lymph node metastases.
There have been conflicting reports about the correla-
tion between CSC marker expression and long term
prognosis in female breast cancers [13,18,26]. Recent
studies showed positive association between ALDH1
expression and prognosis in node positive female breast
cancers [26]. The ALDH1 phenotype is an independent
predictor of early tumor relapse [27]. In our study of
male breast cancer patients, we did not find expression of
two CSC markers, CD44 and ALDH1, to correlate with a
number of prognostic parameters, such as tumor size,
lymph node metastasis, and nuclear and histologic grad-
ing. A limitation of our study includes the lack of long-
term follow-up of these patients and the number of me-
tastatic tumors that we were able to analyze.
5. Conclusion
In summary, in this pilot study we show that CD44 and
ALDH1 are expressed in male breast cancers and they
are overexpressed in invasive cancer compared to carci-
noma in situ. These findings suggest that CSCs play an
important role in the progression to invasive carcinoma.
Interestingly, we find low expression of stromal cells in
patients with metastatic disease.
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