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ORIGINAL PAPER
Tau proteins expressions in advanced breast cancer and itssignificance in taxane-containing neoadjuvant chemotherapy
Zhi-hua Li • Qiu-yun Xiong • Jian-hong Tu •
Yu Gong • Wei Qiu • Hui-qin Zhang •
Wen-shong Wei • Yi-Feng Hou • Wei-qi Cui
Received: 5 April 2013 / Accepted: 23 April 2013 / Published online: 17 May 2013
� Springer Science+Business Media New York 2013
Abstract Tau is a microtubule-associated protein and
expressed in normal breast epithelial cells and breast can-
cer. Tau expression in breast cancer may be important for
chemotherapy optimization. This study is to investigate the
expression of Tau in advanced breast cancer and its sig-
nificance in taxane-containing neoadjuvant chemotherapy.
Levels of Tau protein in advanced breast cancer were
detected immunohistochemically. The chemotherapeutic
efficacy indexes in Tau- group, which includes the
remission rate, Miller-Payne pathological reactive grade,
and pathologic complete response rate, were improved
compared with that in Tau? group. There was difference in
the efficacy indexes among ER? subgroups but not among
ER- patients. In addition, Tau expression was positively
correlated (r = 0.32, P \ 0.00). In multivariate analysis,
when age, clinical stage, postoperative lymph node
metastasis, ER, PR, HER2, Ki-67, TP53, or Tau status were
included, postoperative lymph node metastasis and Tau-
negative status were identified as independent predictors of
pathologic complete response. In conclusion, negative Tau
protein expression may be an effective predictor for tax-
ane-containing neoadjuvant chemotherapy, especially in
ER? subgroups. Further study on the molecular mecha-
nism and utility of Tau for individualizing adjuvant che-
motherapy is warranted.
Electronic supplementary material The online version of thisarticle (doi:10.1007/s12032-013-0591-y) contains supplementarymaterial, which is available to authorized users.
Z. Li � Q. Xiong � Y. Gong � H. Zhang � W. Wei � W. Cui (&)
Prevention and Cure Center of Breast Disease, The Third
Hospital of Nanchang City, Nanchang 330009, JiangXi,
People’s Republic of China
e-mail: [email protected]
Z. Li
e-mail: [email protected]
Q. Xiong
e-mail: [email protected]
Y. Gong
e-mail: [email protected]
H. Zhang
e-mail: [email protected]
W. Wei
e-mail: [email protected]
Z. Li
Oncology Department, The First Affiliated Hospital
of Nanchang University, Nanchang 330009, Jiangxi,
People’s Republic of China
J. Tu � W. Qiu
Pathology Departments, The Third Hospital of Nanchang City,
JiangXi Breast Specialist Hospital, Nanchang 330009, JiangXi,
People’s Republic of China
e-mail: [email protected]
W. Qiu
e-mail: [email protected]
Y.-F. Hou (&)
Department of Breast Surgery, Breast Cancer Institute
Cancer Hospital, Fudan University, 270 Dong’an Road,
Shanghai 200032, People’s Republic of China
e-mail: [email protected]
123
Med Oncol (2013) 30:591
DOI 10.1007/s12032-013-0591-y
Keywords Tau protein � Breast cancer � Taxane �Drug resistance
Abbreviations
ER Estrogen receptor
PR Progesterone receptor
HER Human epidermal growth factor receptor
IHC Immunohistochemistry
FISH Fluorescence in situ hybridization
TAC Cyclophosphamide, epirubicin, and docetaxel
TP53 P53 mutation protein
pCR Pathologic complete response
PINV Presence of invasive carcinoma
Introduction
In the past two decades, the incidence and mortality of
breast cancer have climbed sharply in China [1]. Although
the prognosis for breast cancer has been improved in recent
years, drug resistance is still a problem. Effective predic-
tors of chemotherapy, with higher efficacy and less side
effects, are urgently demanded. Chemotherapy with tax-
anes was developed in the 1970s. Taxanes bind to tubulin
and suppress spindle microtubule dynamics, leading to cell
cycle arrest in G2/M phase, followed by apoptosis [2, 3]. In
the 1990s, these drugs became widely applied in breast
cancer treatment, which effectively improved survival in
some patients. However, recurrence and metastasis still
happened due to the cancer resistance of taxanes. More-
over, for patients with taxane resistance, such regime of
chemotherapy always bring them unnecessary side effects,
such as pain, hematologic toxicity, and extra costs, which
will affect their quality of life [4]. Several biological
indicators for taxanes resistance have been described, such
as MDR-1/P-gp, HER2, P53 mutation protein, and variable
expression of tubulin isotypes [5]. Giannakakou et al. [6]
found that paclitaxel selects for mutant or pseudo-null p53
in drug resistance associated with tubulin mutations in
human cancer. However, others found those clinicopatho-
logical and immunohistochemical parameters, such as ER,
PR, p53, p21, and HER2 protein expression, did not predict
response to therapy, though HER2 protein over-expression
was associated with decreased disease-free and overall
survival by multivariate analysis [7]. Tau is a microtubule-
associated protein. Tau and taxanes compete for the same
binding site in tubulin. Although Tau expression level may
indicate a taxane-resistant phenotype [8], several clinical
studies could not prove predictive value of Tau for pac-
litaxel treatment in breast cancer [9]. The objective of this
current analysis was to investigate expression of Tau in
advanced breast cancer and its significance in taxane-con-
taining neoadjuvant chemotherapy.
Materials and methods
Patients and clinicopathologic characteristics
1986 patients with breast cancer newly diagnosed in the
Third Hospital of Nanchang City during April 2007–
October 2010 were evaluated. Among these, 200 female
patients treated with taxane-containing neoadjuvant che-
motherapy were enrolled in this study. Patients with sys-
temic metastasis or deficient clinical data were excluded.
This study was approved by the Institutional Review Board
of the Third Hospital of Nanchang City. Written informed
consent was obtained from all patients.
The mean age of all patients was 46.8 ± 8.8 years
(range 24–76 years). Staging were determined by using the
criteria of the sixth edition of the AJCC Cancer Staging
Manual [10]. Totally, there were 111 cases with stage IIb,
54 cases with stage IIIa, 22 cases with stage IIIb, and 13
cases with stage IIIc. There were 163 cases of invasive
ductal carcinoma, 11 cases of invasive lobular cancer, 10
cases of mixed histological type, and 16 cases of special
pathological types. Biological information of the patients
included 124 ER? cases and 76 ER- cases, 114 PR?
cases and 86 PR- cases, 55 HER2? cases and 145
HER2- cases, 118 ki-67? cases and 82 ki-67- cases, 83
TP53? cases and 117 TP53-cases. As for surgical pro-
cedures, 13 cases underwent breast-conserving surgery,
159 cases underwent modified radical mastectomy, and 28
cases underwent traditional radical surgery. Clinicopatho-
logic characteristics of these patients were shown in
Table 1.
Neoadjuvant chemotherapy (NACT) and response
criterion
All the patients were diagnosed with invasive breast cancer
using core needle biopsies. They then received three cycles
of TAC as NACT. Patients received cyclophosphamide
500 mg/m2 (CTX, Jiangsu Hengrui Medicine Co., Ltd),
epirubicin 75 mg/m2 (Pharmorubicin, Pfizer), and doce-
taxel 75 mg/m2 (DOC, Shenzhen Main Luck Pharmaceu-
ticals Inc.) every 3 weeks.
The size of the breast lump and axillary nodal status was
determined by ultrasound examination before each cycle
and before surgery. The product of the two largest per-
pendicular diameters was used to approximate tumor area.
In patients with multifocal or multicentric breast cancers,
the lesion with the largest diameter was chosen for follow-
up. Clinical response after three cycles of TAC was eval-
uated according to the following criteria: complete
response (CR) when no breast tumor was palpable; partial
response (PR) when the reduction in the tumor area was
C50 %; no change (NC) when the tumor area was reduced
Page 2 of 7 Med Oncol (2013) 30:591
123
\50 % or increased \25 %, and progressive disease (PD)
was recorded if the tumor area increased C25 %, or if a
new lesion was detected. The histological response was
classified as score of 3, 4, or 5, based on Miller-Payne score
system [11], with 5 being a pathologic complete response
(pCR).
Immunohistochemical studies of ER, PR, HER2, Ki-67,
TP53, and Tau
All core biopsies and surgically excised tumors of the
patients were fixed in formalin and embedded in paraffin
wax. Immunohistochemistry and scoring were performed.
All slides were reviewed by two pathologists (Wei Qiu,
Jian-hong Tu) independently. Tumor samples were cate-
gorized as ER or PR positive if at least 1 % of tumor cells
stained for ER or PR protein, respectively [12]. Ki-67
positive was defined as if no \15 % of cells stained
positive. Scoring of HER-2/neu result was done as sug-
gested for the HercepTest score (US FDA standard) [13],
IHC staining 0 was considered as negative, IHC staining
3? was considered as Her-2/neu?, IHC staining 1–2? was
chosen for HER2 gene amplification testing by fluores-
cence in situ hybridization (FISH). Ratio of HER2 signaling
\1.8 suggested that there is no HER2 gene amplification in
the samples. Ratio [2.2 suggested that HER2 gene
amplification occurred in the samples. When the ratio was
between 1.8 and 2.2, number of cells counted would be
increased to 100, or the experiment was repeated to
determine the final result (Fig. 1).
TP53 immunostaining was done with the DO7 clone
antibody (Novocastra, UK; dilution 1: 250), which was
previously reported to detect most p53 point mutations
[14]. Tumor samples were classified as p53? if they
exhibited at least 10 % of stained cells [15]. Immunohis-
tochemistry for Tau was performed as described previ-
ously, using anti-Tau monoclonal antibody (1:50 dilution,
clone T1029, United States Biological, Swampscott, M A)
[16]. Cytoplasmic expression of Tau protein in normal
breast epithelium was considered internal positive controls
and as reference for scoring. Tau staining of tumor cells
was scored as following: IHC score 0, no staining; IHC 1?,
less staining than normal epithelium; IHC 2?, similar to
normal epithelium; IHC 3?, uniform staining more intense
than normal cells. Cases with IHC scores of 0 or 1? were
considered to be Tau negative, and tumors with scores 2?
or 3? were considered to be Tau positive.
Statistical analysis
All statistical analysis was carried out with SPSS 13.0
software for Windows (SPSS, Inc, Chicago, IL, USA). The
v2 test or Fisher’s exact test was used to compare the
associations between TP53, Tau expression and other
clinical variables; Spearman’s test was used for correlation
analysis; and multivariant logistic regression analysis was
used to relate age, clinical stage, postoperative lymph node
metastasis, ER, PR, HER2, Ki-67, TP53, or Tau status with
clinical or histological response. All P values were based
on two-sided testing, and differences were considered
significant as P \ 0.05.
Results
Expression of Tau in breast cancer and correlation
with TP53 and chemotherapeutic response
In 200 breast cancer patients, 88 (44 %) cases showed Tau
expression, but 83 (41.5 %) showed TP53 protein
Table 1 Clinicopathologic characteristics of patients cohort
Variable N %
Staging
IIb 111 55.5
IIIa 54 37.0
IIIb 22 11.0
IIIc 13 6.5
Histological type
Invasive ductal carcinoma 163 81.5
Invasive lobular cancer 11 5.5
Mixed type 10 5.0
Other types 16 8.0
ER status
ER negative 76 38.0
ER positive 124 62.0
PR status
PR negative 86 43.0
PR positive 114 57.0
HER2 status
HER2 negative 145 72.5
HER2 positive 55 27.5
Ki-67 status
Ki-67 \15 % 82 41.0
Ki-67 C15 % 118 59.0
TP53 status
\10 % 117 58.5
C10 % 83 41.5
Surgical types
Breast conservation 13 6.5
Modified radical mastectomy 159 79.5
Traditionally radical mastectomy 28 14.0
Med Oncol (2013) 30:591 Page 3 of 7
123
expression (Fig. 2a–e). There was no correlation between
them by using Spearman’s correlation analysis (r = -0.03,
P = 0.62).
Patients with high Tau expression showed improved
clinical efficacy, better Miller-Payne pathological reactive
grade, and higher pCR, compared with those with negative
Fig. 1 Detection of HER2 DNA amplification in breast carcinoma by FISH. a Each tumor cell nucleus demonstrated HER2 signals/CEP 17
signals ratio of [2.2 (91,000). b Non-amplified HER2 DNA as demonstrated by HER2/CEP17 ratio \1.8 (91,000)
Fig. 2 Immunohistostaining of Tau, TP53, and ER protein. a Nega-
tive Tau expression in breast cancer (SP 9 200). b Positive Tau
expression in breast cancer (SP 9 200). c Positive Tau expression in
normal breast epithelial cells (SP 9 200). d Negative TP53
expression in breast cancer (SP 9 200). e Positive TP53 expression
in breast cancer (SP 9 200). f Positive ER expression in breast cancer
(SP 9 200)
Page 4 of 7 Med Oncol (2013) 30:591
123
Tau expression (P = 0.002, \0.0001, \0.0001, respec-
tively; Table 2).
Comparison of Tau protein expression between ER?
and ER- patients
When stratified by ER status, Tau expression was positive
correlated with ER expression in breast cancer (r = 0.32,
P \ 0.0001). In ER? subset patients, improved clinical
efficacy, Miller-Payne pathological reactive grade, and
pCR rate were shown in the Tau group compared with
Tau? group (P = 0.01, \0.001, \0.001), although signif-
icant differences were not found in ER- subset patients
(P = 1.00, 0.62, 0.12). All are shown in Table 3.
Multivariate analysis pCR of neoadjuvant
chemotherapy in breast cancer
Thirty-nine patients had pCR (19.5 %) after three cycles of
CET regimens. Univariate logistic regression analysis
including age, clinical stage, postoperative lymph node
metastasis, ER, PR, HER2, Ki-67, P53 mutant protein, and
Tau identified postoperative lymph node metastasis
(P = 0.002), ER (P = 0.001), PR (P = 0.004), HER2
(P = 0.003), and Tau (P = 0.001) as predictive factors
associated with pCR of NACT in breast cancer (Table 4).
In multivariate analysis, postoperative lymph node metas-
tasis (P = 0.009) and Tau-negative status (P = 0.001)
were identified as independent predictors of pCR (Table 5).
Discussion
In the 1970s, Dr Fisher said ‘‘some tumors are metastatic
from the time they are discovered, even though they are
discovered when they are extraordinarily small and barely
recognizable as tumors’’ [17]. Modern science then viewed
breast cancer as a systemic disease; breast cancers were
therefore treated with systemic therapies, such as chemo-
therapy or hormonal therapy. Now chemotherapy is part of
combined treatments for advanced breast cancer. There are
several commonly used combination chemotherapy regi-
mens that are considered acceptable standard adjuvant or
neoadjuvant treatments [18]. More recently, incorporation
of taxanes into anthracycline-containing chemotherapy
regimens has been shown to improve disease-free survival
[19]. Taxanes, paclitaxel, and docetaxel interfere with
spindle microtubule dynamics, causing cell cycle arrest and
apoptosis. However, some patients may not benefit from
these treatments due to chemo-resistance mechanisms.
Tau, a microtubule-associated protein (MAP), may
interact with paclitaxel due to binding to beta-tubulin in the
same point, which may also help determine a taxane-
resistant phenotype [8]. We initially thought the taxane
resistance could reflect an interaction of TP53 protein with
Tau protein, but found no correlation between them (r =
-0.03, P = 0.62). Our study evaluated 200 patients who
received TAC neoadjuvant chemotherapy and found the
remission rate, Miller-Payne pathological reactive grade
and pCR rate in the Tau- group were higher than in the
Table 2 TP53 and Tau expressions in breast cancer and neoadjuvant chemotherapy efficacy
Miller-Payne Response rate pCR
G1–2 G3–5 v2 P CR ? PR SD ? PD v2 P pCR PINV v2 P
Tau- 12 100 24.63 0 106 6 9.44 0.0001 35 77 22.4 0.0001
Tau? 36 52 71 17 4 84
Table 3 TP53 and Tau expressions and neoadjuvant chemotherapy results in ER? and ER- breast cancer patients
Tumor subgroup Number of patients pCR P CR ? PR P Miller-Payne G3-5 P
n % n % n %
ER- breast cancer patients
Tau
- 58 21 36.20 0.12 55 94.80 1.00a 54 98.20 0.62a
? 18 3 16.70 17 94.40 0.669 16 88.90
ER? breast cancer patients
Tau
– 54 14 25.90 0 51 94.40 0.008 46 85.20 0
? 70 1 1.40 54 77.10 7.033 36 51.4 %
a Fisher’s exact test
Med Oncol (2013) 30:591 Page 5 of 7
123
Tau? group (P = 0.002, \0.0001, \0.0001, respectively).
Thus, low Tau protein expression in breast cancer may
predict taxane response, which was confirmed in experi-
ments with cells, animal models, and some clinical studies
[16, 20–25], but not supported by some retrospective
analyses [26, 27].
Different predictive or prognostic markers have been
suggested for different molecular subsets of breast cancer.
Expression of Tau in breast cancer may be affected by ER
[28]. In this study, there were 124 cases of ER? patients,
which included 70 Tau protein? cases and 54 Tau pro-
tein- cases. Tau expression was found to be positively
correlated with ER expression in breast cancer (r = 0.32,
P \ 0.0001). The correlation was also confirmed by Andre
et al. [23]. Pusztai et al. retrospectively analyzed 1942
breast cancer patients and found ER? tumors with high
Tau expression are sensitive to hormonal therapy, but
respond poorly to paclitaxel-based chemotherapy. In ER-
tumors, Tau’s prognostic value was unconfirmed, though a
non-significant trend of better response to paclitaxel was
noticed [27]. We found Tau’s predictive value only in the
ER? subgroup and not in the ER- subgroup, which was
consistent with Pusztai’s conclusion [27]. However, both in
ER? and ER- tumors, p53 status was not related to taxane
response, which further validated our conclusion. Multi-
variate analysis showed Tau-negative status as independent
predictors of pCR, which indicated the predictive value of
Tau-negative status was not because it is related with other
index, such as ER, HER2, proliferation index.
Of course, the debate of the predictive value of Tau
protein for taxane-contained chemotherapy will continue,
as there are several reasons for the disagreement. First,
there are disparities between RNA and protein expression
in breast cancer [29]. Second, mechanisms of resistance are
complex and hard to explain on the basis of one marker [9].
Furthermore, sampling error and analysis bias may lead to
a different conclusion. Patients with HER2 molecular
subtype breast cancer can achieve better remission rate and
pCR rate [30]. In our study, Tau– tumors included 32 cases
of the HER2 molecular subtype, accounting for 28.57 %
(32/112) [Table S1], which was higher than one reported
rate [31]. Therefore, the predictive significance of Tau
should be evaluated in well-projected prospective studies.
In summary, the present study shows Tau expression
may be an independent effective predictor for taxane-
containing chemotherapy in breast cancer, and the predic-
tive value may be more obvious in ER? breast cancer.
Detection of Tau protein expression in breast cancer may
be a factor in choosing taxane-containing chemotherapy.
Further study on the molecular mechanism and utility of
Tau for individualizing adjuvant chemotherapy is
warranted.
Acknowledgments We thank the studied women for willingness to
cooperate with our study. This work was supported by Nanchang key
research project funded (Contract Grant Numbers: 2010-95), the
National Natural Science Foundation of China (Contract Grant
Numbers: 81072165, 81260389), and the Shanghai Science and
Technology Committee (Contract Grant Numbers: 09PJ1402700).
Conflict of interest The authors declare that they have no com-
peting interests.
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