The role of adipocytokines in breast cancer

1
The role of adipocytokines in breast cancer

• ???????????
• ?????????
• ???

2
Overview of breast cancer

• Breast cancer is a malignant tumor which severely
  impairs the woman health. According to the
  statistics of Department of Health from 1995 to
  2007, breast cancer has jumped to the first place
  in the incidence of women-specific malignancies
  in Taiwan, and growing at a surprising rapidity.
• Known breast cancer risk factors include age,
  family or personal history of breast cancer, high
  breast tissue density, atypical hyperplasia, a
  history of chest radiation, early menarche,
  recent use of oral contraceptive drugs, age of
  birth of first child over 30, obesity after
  menopause (Willett et al., 2004 Viswanathan et
  al., 2009). It is a critical issue to explore the
  underlying mechanisms for female breast cancer in
  Taiwan and to discover the prognostic factors and
  therapeutic targets for Taiwanese breast cancer.

3

• The etiology of breast cancer is still poorly
  understood, but several risk factors are well
  confirmed, including increasing age, geographic
  location (USA and western countries), familial
  history of breast cancer, genetic mutations
  (BRCA1, BRCA2, p53, ATM NBS1, LKB1), ionizing
  radiation exposure, history of benign breast
  disease, increased mammographic density, early
  menarche and late menopause, nulliparity and old
  age at first delivery, exogenous hormone usage,
  lifestyle (alcohol, diet, obesity and physical
  activity), high IGF-1 and prolactin levels, etc.
  (Collaborative Group on Hormonal Factors in
  Breast Cancer, 2001 Dumitrescu and Cotarla,
  2005).

4
Adipocytokines

• Adipose tissue is no longer considered to be an
  inert tissue functioning solely as an energy
  store, but is emerging as an important factor in
  the regulation of many pathological processes.
  Various products of adipose tissue have been
  characterized, and some of the soluble factors
  produced by this tissue are known as
  adipocytokines (Calle and Kaaks 2004).
• The term adipocytokine is used to describe
  certain cytokines that are mainly produced by
  adipose tissue, although it is important to note
  that they are not all exclusively derived from
  this tissue (Wellen and Hotamisligil 2005).

5

• Adiponectin, leptin, resistin and visfatin are
  adipocytokines and are thought to provide an
  important link between obesity, insulin
  resistance and related inflammatory disorders
  (Herbert Tilg and Alexander R. Moschen, 2006).
• The incidence of obesity and its associated
  disorders are increasing markedly worldwide.
  Obesity predisposes individuals to an increased
  risk of developing many diseases, including
  atherosclerosis, diabetes, nonalcoholic fatty
  liver disease, certain cancers and some
  immune-mediated disorders (Mannino, Mott et al.
  2006).

6
Resistin (also known as FIZZ3), which is a
114-amino-acid polypeptide, was originally shown
to induce insulin resistance in mice80. It
belongs to a family of cysteine-rich proteins,
also known as resistin-like molecules (RELMs),
that have been implicated in the regulation of
inflammatory processes79. Resistin was shown to
circulate in two distinct forms a more prevalent
high-molecular-weight hexamer and a substantially
more bioactive, but less prevalent,
low-molecular-weight complex82.
Fig.1 Adipose tissue cellular components and
molecules synthesized. (Herbert Tilg and
Alexander R. Moschen, 2006)
7
(Marra and Bertolani 2009)
8
(Herbert Tilg and Alexander R. Moschen, 2006)
9

• Adipocytokines function as hormones to influence
  energy homeostasis and to regulate neuroendocrine
  function. As cytokines, they affect immune
  functions and inflammatory processes throughout
  the body. The field of adipocytokines has
  attracted tremendous interest recently and the
  knowledge that has accumulated might lead to the
  development of new therapeutics (Herbert Tilg and
  Alexander R. Moschen, 2006).

10

• Obesity is a serious health problem in the
  industrialized world. Also, similar trends have
  been observed in many developing countries
  (Shetty and Schmidhuber 2006). Obesity is
  associated with a number of disorders including
  cardiovascular disease, hypertension, Type 2
  diabetes, dyslipidemia and cancer (Hanif and
  Kumar 2002).
• Probably, a large number of cancers are linked
  with obesity such as cancers of the colon, breast
  (postmenopausal), endometrium, kidney, esophagus
  and gastric cardia (adenocarcinoma), gall
  bladder, liver, pancreas, prostate (advanced
  malignancy), ovary and hematopoietic tissues like
  non-Hodgkin's lymphoma (NHL), multiple myeloma
  and leukemia (Calle 2007).

11

• Furthermore, it is worthy to mention that obesity
  may influence prognosis through various
  mechanisms, including co-morbidities and
  endocrine factors (McTiernan 2005). In addition
  to serve as an energy depot, adipose tissue or
  fat mass releases several hormone-like chemicals
  or adipokines, which perhaps provide a link among
  cancer, insulin resistance, inflammation and
  oxidative stress (Ruan and Lodish 2004).
• Here, we provide an overview of recent advances
  in our view of the role of adipocytokines in
  breast cancers.

12

• Figure 1 Effects of obesity on the pathological
  processes that favor carcinogenesis (Murthy,
  Mukherjee et al. 2009)

13
(No Transcript)
14
Increased resistin and its association with
positive ER status in breast cancer is associated
with a poor overall survival
15
Resistin

• Resistin, a 12.5 kDa protein and named for
  resistance to insulin, is a signaling molecule
  secreted from adipocytes. It is expressed in
  adipocytes, muscle, pancreatic cells, and mRNA
  displays an even wide range, having been found in
  white fat, spleen, hypothalamus, adrenal gland,
  skeletal muscle, gastrointestinal tract, and
  pancreas (Wozniak et al., 2009).
• Resistin serves as a hormone (Steppan et al.,
  2001), that could decrease the sensitivities of
  insulin in the adipose cells so that insulin
  resistance is formed (Steppan and Lazar, 2004).

16

• Circulating resistin levels are decreased by the
  anti-diabetic drug, increased in diet-induced and
  genetic forms of obesity. Insulin-stimulated
  glucose uptake by adipocytes is enhanced by
  neutralization of resistin and is reduced by
  resistin treatment (Kang et al., 2006).
• In cancer studies, human serum resistin levels
  are significantly increased in breast cancer
  patients as compared to controls, especially
  after menopause, and correlated with the size of
  tumor. In addition, resistin concentration in
  lymph node metastasis group is higher than that
  in the group without lymph node metastasis,
  suggest that resistin may promote metastasis of
  breast cancer cells (Hou et al., 2007).

17
Fig.3 Effects of various adipocytokines on the
monocytemacrophage system. c The receptor for
resistin is unknown, but this adipocytokine
induces the activation of p38, ERK and
phosphatidylinositol 3-kinase (PI3K). Resistin
increases the production of TNF, IL-1ß, IL-6 and
IL-12. Its effect on monocyte and macrophage
functions is not known. Whereas adiponectin can
be considered an anti-inflammatory strategy of
the adipose organ, leptin and resistin have
dominant pro-inflammatory features (Herbert Tilg
and Alexander R. Moschen, 2006).
18

• To determine the expression profiles of resistin
  in breast cancer and their correlation with
  prognosis and other clinico-pathological
  parameters.

Positive gt 30
19
Table 1. Correlation of resistin expression in
the serum of breast cancer and non breast cancer.
Breast
cancer (n81) Non breast cancer
(n81) P value
Resistin (MeanSD) 30.78 8.59 ng/ml
26.915.00 ng/ml
0.001
The P value was calculated by the t-test.
20
Table 2. Clinicopathological characteristics in breast cancer. Table 2. Clinicopathological characteristics in breast cancer. Table 2. Clinicopathological characteristics in breast cancer.
Characteristics patients with breast cancer of patients (n81)
Stage
I 39 48.1
II 31 38.3
III 11 13.6
Grade
I 9 11.1
II 54 66.7
III 18 22.2
Age
?50 39 48.1
gt50 42 51.9
LN Metastasis
Negative 56 69.1
Positive 25 30.9
ER
Negative 29 35.8
Positive 52 64.2
PR
Negative 40 49.4
Positive 41 50.6
Her2/Neu
Negative 50 61.7
Positive 31 38.3
21
Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer. Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer. Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer. Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer.
resistin resistin
Characteristics ?27 ng/ml () gt27 ng/ml () P value
Stage
I 11 (28.2) 28 (71.8) 0.413
II 7 (22.6) 24 (77.4)
III 1 (9.1) 10 (90.9)
Grade
I 1 (11.1) 8 (88.9) 0.618
II 14 (25.9) 40 (74.1)
III 4 (22.2) 14 (77.8)
Age
?50 8 (20.5) 31 (79.5) 0.547
gt50 11 (26.2) 31 (73.8)
LN Metastasis
Negative 17 (30.4) 39 (69.6) 0.028
Positive 2 (8.0) 23 (92.0)
ER
Negative 11 (37.9) 18 (62.1) 0.022
Positive 8 (15.4) 44 (84.6)
PR
Negative 13 (32.5) 27 (67.5) 0.058
Positive 6 (14.6) 35 (85.4)
Her2/Neu
Negative 14 (28.0) 36 (72.0) 0.220
Positive 5 (16.1) 26 (83.9)

The P value was calculated by the chi-square
test.
22
Fig. 2 The average tumor size (cm in diameter)
for breast patients with low and high resistin
expression. The average tumor size was 2.710.27
cm for low resistin expression (n19) and
2.860.18 cm for high resistin expression (n62)
in breast cancer, P0.689. Values were expressed
as MeanSEM determined by independent-samples t
test.
23
P0.033
Fig. 3 KaplanMeier survival curves are shown for
the low and high resistin expression groups in
breast cancer.
24
P 0.108
Fig. 4 KaplanMeier survival curves are shown for
the low and high resistin expression groups
combined with positive and negative ER status in
breast cancer.
25
Table 5. Cox regression multivariate analysis of overall survival for breast cancer. Table 5. Cox regression multivariate analysis of overall survival for breast cancer. Table 5. Cox regression multivariate analysis of overall survival for breast cancer.
Variables Odds ratio (95 CI) P value
Tumor stage (I/II/III) 3.203 (1.386-7.403) 0.006
Tumor grade (I/II/III) 2.088 (0.713-6.115) 0.179
Age (gt 50 years) 0.676 (0.229-1.993) 0.478
ER status (Negative/Positive) 2.420 (0.788-7.433) 0.123
PR status (Negative/Positive) 1.345 (0.377-4.803) 0.648
Her2/Neu status (Negative/Positive) 1.139 (0.864-1.500) 0.356
Resistin expression (Low/High) 15.373 (1.629-145.098) 0.017
26
Fig. 1 Immunohistochemistry showing high (A) and
low (B) expression of resistin in breast cancer
tissue. (C) normal breast tissue, (D) negative
control. Original magnification was X100.
27
Table 1. Immunohistochemistry of resistin
expressions in breast cancer and adjacent normal
breast tissue.
Breast cancer
tissue (n37) Adjacent normal breast
tissue (n37) P value

Resistin
33 (89.2)
lt0.001
4 (10.8)
18 (48.6) 19 (51.4)
Low-expression High-expression
The P value was calculated by the chi-square
test.
28
Table 2. Clinicopathological characteristics in breast cancer. Table 2. Clinicopathological characteristics in breast cancer. Table 2. Clinicopathological characteristics in breast cancer.
Characteristics patients with breast cancer of patients (n108)
Stage
I 55 50.9
II 40 37.0
III 13 12.0
Grade
I 12 11.1
II 71 65.7
III 25 23.1
Age
?50 53 49.1
gt50 55 50.9
LN Metastasis
Negative 76 71.4
Positive 32 29.6
ER
Negative 40 37.0
Positive 68 63.0
PR
Negative 52 48.1
Positive 56 51.9
Her2/Neu
Negative 67 62.0
Positive 41 38.0
29
Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer. Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer. Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer. Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer. Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer.
resistin resistin resistin
Characteristics Low () High () P value
Stage
I 23 (41.8) 32 (58.2) 0.061
II 8 (20.0) 32 (80.0)
III 3 (23.1) 10 (76.9)
Grade
I 4 (33.3) 8 (66.7) 0.277
II 19 (26.8) 52 (73.2)
III 11 (44.0) 14 (56.0)
Age
?50 22 (41.5) 31 (58.5) 0.028
gt50 12 (21.8) 43 (78.2)
LN Metastasis
Negative 28 (36.8) 48 (63.2) 0.065
Positive 6 (18.8) 26 (81.2)
ER
Negative 18 (45.0) 22 (55.0) 0.020
Positive 16 (23.5) 52 (76.5)
PR
Negative 20 (38.5) 32 (61.5) 0.132
Positive 14 (25.0) 42 (75.0)
Her2/Neu
Negative 20 (29.9) 47 (70.1) 0.641
Positive 14 (34.1) 27 (65.9)

The P value was calculated by the chi-square
test.
30
Fig. 2 The average tumor size (cm in diameter)
for breast patients with low and high resistin
expression. The average tumor size was 1.790.15
cm for low resistin expression (n34) and
2.290.14 cm for high resistin expression (n74)
in immunohistochemistry analysis groups,
P0.017. Values were expressed as MeanSEM
determined by independent-samples t test.
31
P0.003
Fig. 3 KaplanMeier survival curves are shown for
the low and high resistin expression groups,
determined by immunohistochemistry analysis.
32
P0.004
Fig. 4 KaplanMeier survival curves are shown for
the low and high resistin expression groups
combined with positive and negative ER,
determined by immunohistochemistry analysis.
33
Table 4. Cox regression multivariate analysis of overall survival for breast cancer. Table 4. Cox regression multivariate analysis of overall survival for breast cancer. Table 4. Cox regression multivariate analysis of overall survival for breast cancer.
Variables Odds ratio (95 CI) P value
Tumor stage (I/II/III) 2.791 (1.291-6.036) 0.009
Tumor grade (I/II/III) 4.448 (1.400-14.129) 0.011
Age (gt 50 years) 0.285 (0.073-1.111) 0.071
ER status (Negative/Positive) 1.282 (0.877-1.873) 0.199
PR status (Negative/Positive) 1.174 (0.839-1.643) 0.349
Her2/Neu status (Negative/Positive) 1.192 (0.943-1.507) 0.142
Resistin expression (Low/High) 11.250 (1.216-104.077) 0.033
34
Conclusion

• Altered resistin expression may be involved in
  the pathogenesis of breast cancer in an
  ER-dependent manner.
• Adipocytokines could be attractive candidates as
  the missing link between obesity and cancer.

35

• Altered visfatin expression in breast cancer
  tissue is associated with a poor overall survival

36
Visfatin

• Visfatin, a 52 kDa protein and produced by
  lymphocytes (Fukuhara et al., 2005), has
  nicotinamide adenine dinucleotide (NAD)
  biosynthetic activity, which is essential for
  B-cell maturation and function (Samal et al.,
  1994 2003 Revollo et al., 2007).
• Recently, visfatin has been identified as an
  adipocytokine hormone that could make adipose
  cells to increase the sensitivity of insulin
  (Fukuhara et al., 2005) and associated with
  obesity, type II diabetes and rheumatoid
  arthritis (Brentano et al., 2007).

37

• In human studies, a positive correlation between
  visfatin gene expression in visceral adipose
  tissue and body mass index (BMI) is noted, along
  with negative correlation between BMI and
  subcutaneous fat visfatin (Berndt et al., 2005),
  suggesting that visfatin regulation in these
  different depots is different, and adipose depot
  ratios are highly dependent on the obesity of the
  subjects.
• In breast cancer studies, visfatin is reported to
  be expressed in doxorubicin-responsive breast
  cancer (Folgueira et al., 2005), and have
  demonstrated that visfation mRNA and protein
  expressed in MCF-7 breast cancer cells.
  Furthermore, visfatin is present in bovine
  mammary epithelial cells, lactating mammary gland
  and milk (Yonezawa et al., 2006). These studies
  suggest that visfatin may be plays some important
  role in the mammary epithelial cells and mammary
  gland.

38

• (Hausenloy 2009)

39

• To determine the expression profiles of visfatin
  in breast cancer and their correlation with
  prognosis and other clinico-pathological
  parameters.

Positive gt 30
40
Table 1. Correlation of visfatin expression in
the serum of breast cancer and non breast cancer.
Breast cancer (n68) Non breast cancer (n68) p value
Visfatin (MeanSD) 39.98 22.09 ng/ml 31.9219.90 ng/ml 0.007
The P value was calculated by the T-test.
41
Table 2. Clinicopathological characteristics in breast cancer. Table 2. Clinicopathological characteristics in breast cancer. Table 2. Clinicopathological characteristics in breast cancer.
Characteristics patients with breast cancer of patients (n68)
Stage
I 37 54.4
II 23 33.8
III 8 11.8
Grade
I 6 8.8
II 45 66.2
III 17 25.0
Age
?50 36 52.9
gt50 32 47.1
LN Metastasis
Negative 49 72.1
Positive 19 27.9
ER
Negative 25 36.8
Positive 43 63.2
PR
Negative 30 44.1
Positive 38 55.9
Her2/Neu
Negative 44 64.7
Positive 24 35.3
42
Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer. Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer. Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer. Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer.
visfatin visfatin
Characteristics ?32 ng/ml () gt32 ng/ml () P value
Stage
I 20 (54.1) 17 (45.9) 0.084
II 9 (39.1) 14 (60.9)
III 1 (12.5) 7 (87.5)
Grade
I 4 (66.7) 2 (33.3) 0.285
II 17 (37.8) 28 (62.2)
III 9 (52.9) 8 (47.1)
Age
?50 18 (50.0) 18 (50.0) 0.300
gt50 12 (37.5) 20 (62.5)
LN Metastasis
Negative 26 (53.1) 23 (46.9) 0.017
Positive 4 (21.1) 15 (78.9)
ER
Negative 7 (28.0) 18 (72.0) 0.041
Positive 23 (53.5) 20 (46.5)
PR
Negative 9 (30.0) 21 (70.0) 0.037
Positive 21 (55.3) 17 (44.7)
Her2/Neu
Negative 22 (50.0) 22 (50.0) 0.186
Positive 8 (33.3) 16 (66.7)
The P value was calculated by the chi-square test. The P value was calculated by the chi-square test. The P value was calculated by the chi-square test. The P value was calculated by the chi-square test.
43
Fig. 1 The average tumor size (cm in diameter)
for breast patients with low and high resistin
expression. The average tumor size was 2.610.17
cm for low resistin expression (n30) and
2.880.20 cm for high resistin expression (n38)
in serum analysis groups, P0.341. Values were
expressed as MeanSEM determined by
independent-samples t test.
44
P0.021
Fig. 2 KaplanMeier survival curves generated by
the low and high visfatin expression groups.
45
P0.002
Fig. 3 KaplanMeier survival curves generated by
the low and high visfatin expression groups
combined with positive and negative ER status.
46
P0.004
Fig. 4 KaplanMeier survival curves generated by
the low and high visfatin expression groups
combined with positive and negative PR status.
47
Table 4. Cox regression multivariate analysis of
overall survival for breast cancer
Variables Odds ratio (95 CI) P Value Variables Odds ratio (95 CI) P Value Variables Odds ratio (95 CI) P Value
Tumor stage (I/II/III) Tumor grade (I/II/III) Age (gt50 years) ER status (negative/positive) PR status (negative/positive) Her2/Neu status (negative/positive) Visfatin expression (High/Low) 12.38 (3.14-48.93) 7.34 (1.10-49.16) 0.07 (0.01-0.77) 8.37 (0.84-83.68) 1.31 (0.63-2.75) 1.21 (0.58-2.49) 29.47 (2.72-319.96) lt0.001 0.040 0.029 0.070 0.472 0.613 0.005
48
A
B
C
D
Fig. 1 Immunohistochemistry showing high (A) and
low (B) expression of visfatin in breast cancer
tissue. (C) normal breast tissue, (D) negative
control. Original magnification was X100.
49
Table 1. Immunohistochemistry of visfatin
expressions in breast cancer and adjacent normal
breast tissue (n45).
Breast cancer tissue () Adjacent normal breast tissue () P value Breast cancer tissue () Adjacent normal breast tissue () P value Breast cancer tissue () Adjacent normal breast tissue () P value
Visfatin Visfatin Visfatin
Low-expression High-expression 29 (64.4) 16 (35.6) 41 (91.1) 0.002 4 (8.9)
The P value was calculated by the chi-square
test.
50
Table 2. Clinicopathological characteristics in breast cancer. Table 2. Clinicopathological characteristics in breast cancer. Table 2. Clinicopathological characteristics in breast cancer.
Characteristics patients with breast cancer of patients (n98)
Stage
I 53 54.1
II 34 34.7
III 11 11.2
Grade
I 7 7.1
II 65 66.3
III 26 26.5
Age
?50 51 52.0
gt50 47 48.0
LN Metastasis
Negative 72 73.5
Positive 26 26.5
ER
Negative 37 37.8
Positive 61 62.2
PR
Negative 42 42.9
Positive 56 57.1
Her2/Neu
Negative 64 65.3
Positive 34 34.7
51
Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer. Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer. Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer. Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer.
visfatin visfatin visfatin
Characteristics Low () High () P value
Stage
I 31 (58.5) 12 (41.5) 0.284
II 14 (41.2) 20 (58.8)
III 6 (54.5) 5 (45.5)
Grade
I 3 (42.9) 4 (51.7) 0.641
II 36 (55.4) 29 (44.6)
III 12 (46.2) 14 (53.8)
Age
?50 31 (60.8) 20 (39.2) 0.071
gt50 20 (42.6) 27 (57.4)
LN Metastasis
Negative 41 (56.9) 31 (43.1) 0.106
Positive 10 (38.5) 16 (61.5)
ER
Negative 13 (35.1) 24 (64.9) 0.009
Positive 38 (62.3) 23 (37.7)
PR
Negative 16 (38.1) 26 (61.9) 0.017
Positive 35 (62.5) 21 (37.5)
Her2/Neu
Negative 30 (46.9) 34 (53.1) 0.160
Positive 21 (61.8) 13 (38.2)
The P value was calculated by the chi-square test. The P value was calculated by the chi-square test. The P value was calculated by the chi-square test.
52
Fig. 2 The average tumor size (cm in diameter)
for breast patients with low and high visfatin
expression. The average tumor size was 1.970.14
cm for low visfatin expression (n51) and
2.630.25 cm for high visfatin expression (n47),
P0.024. Values were expressed as MeanSEM
determined by independent-samples t test.
53
P0.005
Fig. 3 KaplanMeier survival curves generated by
the low and high visfatin expression groups.
54
P0.001
Fig. 4 KaplanMeier survival curves generated by
the low and high visfatin expression groups
combined with positive and negative ER status.
55
P0.005
Fig. 5 KaplanMeier survival curves generated by
the low and high visfatin expression groups
combined with positive and negative PR status.
56
Table 4. Cox regression multivariate analysis of
overall survival for breast cancer
Variables Odds ratio (95 CI) P Value Variables Odds ratio (95 CI) P Value Variables Odds ratio (95 CI) P Value
Tumor stage (I/II/III) Tumor grade (I/II/III) Age (gt50 years) ER status (negative/positive) PR status (negative/positive) Her2/Neu status (negative/positive) Visfatin expression (High/Low) 14.49 (2.65-79.19) 1.90 (0.57-6.39) 1.22 (0.20-7.41) 5.60 (0.34-92.57) 1.70 (0.07-39.45) 1.24 (0.78-1.99) 14.40 (1.33-155.90) 0.002 0.298 0.827 0.228 0.742 0.367 0.028
57
Conclusion

• The elevated expression of visfatin may play a
  role in the carcinogenesis of breast cancer and
  the visfatin may serve as an independent
  prognostic factor for breast cancer.
• Further investigations are required to better
  understand the detailed mechanisms of visfatin
  signaling in breast cancer development.

58
Acknowledgements
National Yang-Ming University
Department of Biomedical Imaging and Radiological
Science, Hsin-Ell Wang.
National Chiao-Tung University
Department of Biological Science and Technology,
Yun-Ming Wang and Jinn-Moon Yang.
Kaohsiung Medical University
General Surgery and Cancer Center, Ming-Feng Hou.

Graduate Institute of Nature Products, Yang-Chag
Wu.
Chang Gung University
Graduate Institute of Nature Products, Pei-Wen
Hsieh.
I-Shou University
Department of Medical Nutrition, Jer-Yiing Houng
.
E-DA Hospital
Chest Surgery, Yu-Jen Cheng and Kun-Chou Hsin.
General Surgery, Chao-Ming Hung and Liu Xian .
Colorectal Surgery, Shin-Pao Chen .
Medical Research, Ya-jing XIE .
59
(No Transcript)
60
Thank you for your attention