Journal of Cancer Therapy, 2012, 3, 755-767
http://dx.doi.org/10.4236/jct.2012.325095 Published Online October 2012 (http://www.SciRP.org/journal/jct)
755
The Role of Heat Shock Proteins in Mammary Neoplasms:
A Brief Review
Leonardo Della Salda, Mariarita Romanucci
Department of Comparative Biomedical Sciences, Faculty of Veterinary Medicine, University of Teramo, Italy.
Received July 13th, 2012; revised August 15th, 2012; accepted August 26th, 2012
ABSTRACT
Research into heat shock proteins (HSPs) for the clinical management of tumours has intensified as new evidence
shows they can be used as biomarkers in carcinogenesis and are related to poor prognosis in some cancer types. Mem-
bers of small HSP, HSP70 and HSP90 families have been studied extensively in breast cancer. This article reviews cur-
rent understanding of the role of HSP and HSF-1 (Heat shock factor 1) expression in human breast cancer and looks at
its potential diagnostic, prognostic and therapeutic value. The exciting progress that has been made using HSP 90 in-
hibitors in breast cancer treatment is examined and the results of preliminary studies on the expression of stress proteins
in the animal model canine mammary tumours are also presented.
Keywords: Cancer; Stress Proteins; Stress Response; Mammary Tumour; Heat Shock Proteins
1. Introduction
Heat shock proteins (HSPs) are a highly conserved class
of proteins normally expressed at low levels by all known
eukaryote and prokaryote cells [1]. Their induction is
mainly dependent on the activation of heat shock factor 1
(HSF-1) and its interaction with heat-shock regulatory
elements (HSEs) present in the promoters of all HSP
genes. HSPs are classified into several families accord-
ing to their approximate molecular weight although a
new nomenclature has recently been proposed [2,3]. HSPs
often act in concert, in large multiprotein complexes
known as molecular chaperones guiding the normal fold-
ing, intracellular disposition and proteolytic turnover of
many of the key regulators of cell growth, differentiation
and survival [4]. However, these functions are altered in
oncogenesis allowing malignant transformation [5] with
upregulation of stress-related genes and increased syn-
thesis of intracellular and extracellular HSPs [6]. This
results in HSPs being tumour-protective through mecha-
nisms such as anti-oxidative processes, the prevention of
protein denaturation, anti-apoptotic activity, and possibly
the direct suppression of the immune system [7]. It has
also been shown that stress proteins, including HSP70,
participate in the folding of numerous protooncogene and
oncogene products [8].
Small HSP, HSP70 and HSP90 families are involved
in the regulation of oestrogen receptors (ER) and hence
have been extensively studied in human breast cancer
where they play a role in tumour cell proliferation, dif-
ferentiation, invasion, metastasis, cell death and tumour
immune response [9,10]. In particular, HSP27 and HSP70
have been shown to exert a pro-malignant effect in breast
cancer, by blocking programmed cell death and se-
nescence, while HSP 90 fosters the accumulation of
mutated or overexpressed oncoproteins. Elevated expres-
sion of HSPs has also been observed in canine mammary
tumours [11,12] and given that these tumours share
many of the epidemiological, clinical-pathological and
biochemical features of human breast cancer, study of the
canine model may prove useful in understanding the mo-
lecular mechanisms involved in mammary carcinogene-
sis [13,14].
2. The Role of HSPs in Mammary Tumour
Cell Proliferation
As mentioned earlier, recent data have shown that chap-
erones facilitate the malignant transformation of mam-
mary cells at a molecular level and their altered utiliza-
tion during oncogenesis is critical in the development of
human breast cancer [15]. The expression of HSPs in
breast cancer is correlated with increased cell prolifera-
tion and it has been shown that selective depletion of
several HSPs results in activation of the apoptotic event
[16]. Multi-protein complexes containing isoforms of
HSP70 and HSP90 and other HSPs or molecular cofac-
tors such as CDC37, P23, CHIP, Tah1, Pih1p and im-

The Role of Heat Shock Proteins in Mammary Neoplasms: A Brief Review
756
munophilins [17,18], have been shown to play an impor-
tant role in the regulation of the cell cycle, controlling the
activity of several signalling proteins [19], especially
cyclins [20] and retinoblastoma protein (pRb), by bind-
ing to these clients and regulating their stability and
function [21]. This interaction is transient in nature and
driven by rounds of adenosine triphosphate (ATP) hy-
drolysis [22]. The high expression of the HSP72/73 in
nucleus of canine mammary tumour cells characterised
by intense proliferation activity and in mitotic cells cor-
roborates the roles exerted by these chaperones in cell
cycle control and in regulating the assembly of mitotic
apparatus [12]. HSP90 client proteins include known
substrates that are key components of the cellular apop-
totic and signal transduction pathways involved in breast
tumour (Wnt, ErbB and Notch), such as mutated p53,
Bcr-Abl, HER2/Neu (ErbB2) and HIF-1α [23] steroid
hormone receptors, Raf-1, Wee-1 and serine/threonine
and tyrosine protein kinases (e.g. Akt kinases), which are
critically dependent on HSPs for their maturation and
conformational maintenance [24,25] (Figure 1(a)). HSP27
and heat shock transcription factor 1 (HSF-1) have been
shown to specifically interact with betacatenin, a pivotal
member of molecular pathways involved in tumour cell
survival [26]. HSF-1 plays a key role in the development
of tumours associated with activation of Ras or inactiva-
tion of p53 and is also critical in the proliferation of
HER2-expressing breast cancer cells, probably because it
maintains the levels of HSPs (HSP72 and HSP27 in par-
ticular), which in turn control regulators of senescence
p21 and survivin [27]. HSPs inhibit apoptosis by func-
tioning at multiple points in the apoptotic signalling
pathways, modulating both intrinsic and extrinsic path-
ways [28-30]. HSP27 binds to cytocrome c [31] whilst
HSP70 and HSP90 bind to Apaf-1 preventing caspase 9
maturation [32]. In contrast, HSP60 and HSP10 promote
the direct proteolytic maturation of caspase 3 (proapop-
totic function). HSP27 inhibits the Daxx apoptotic path-
way [33], while HSP70 binds to JNK1 resulting in inhi-
bition of JNK activation. HSP90 interacts with RIP 1
kinase and AKT [34,35] resulting, in both cases, in the
promotion of NF-κB mediated inhibition of apoptosis. A
similar pattern of change in HSP70, HSP90 and caspases
3 and 8 or other apoptosis-associated proteins, such as
Bcl-2, Bcl-XL, Bax, in both human and canine mam-
mary tumours has also been demonstrated [11]. A direct
relation between HSPs and BRCA1 (BReast-CAncer
susceptibility gene 1) was also highlighted when a DU-
145 cell culture expressing exogenous wild-type BRCA1
(wtBRCA1) showed two to four-fold increased expres-
sion of the HSP27 [36]. Breast cancer metastasis sup-
pressor 1 (BRMS1), a protein that suppresses metastasis
in multiple systems without blocking tumour genesis, is
stabilized by the HSP40, -70, and -90 chaperone complex
[37].
3. Diagnostic and Prognostic Implications of
HSP Expression in Mammary Cancer
HSP expression in breast cancer has been analyzed in
relation to the histopathological characteristics of tumour
tissues e.g. tumour type, grade of differentiation, degree
of proliferation and patient parameters [38-43] but this
has not proved to be particularly informative on a diag-
nostic level and cannot be relied upon for the recognition
of a specific tumour histological type also in canine
mammary tumors [12].
HSP27 expression has been extensively studied given
its relationship with a cytosolic oestrogen receptor-asso-
ciated protein, its physiological role in the assembly and
trafficking of steroid receptors and correlation with oes-
trogen receptor levels [44,45]. However this protein has
not been associated with progesteron receptor in female
cancers or with ERα in male breast carcinomas [46,47].
In addition, other findings indicate that not all ER-posi-
tive breast tumours express HSP27 [44]. It has been re-
ported by some authors that there is no significant or
marginal correlation between HSP27 expression and his-
tological grade or with the proliferation marker ki-67
[48] in well differentiated tumours, however other au-
thors have reported that HSP27 can be directly correlated
to the grade of differentiation both in human and canine
breast tumour [12, 49,50]. In breast cancer the increased
expression of HSP27, apart from the transcriptional acti-
vation via HSF-1, is directly and indirectly (via inter-
action with the oestrogen receptor) activated by Brn-3b
POU transcription factor [51], which is responsible for an
increased growth rate and higher proliferative activity in
mammary cancer cells [52].
Clinical-pathological studies have shown that the in-
ducible form of the HSP70 family (HSP72) is associated
with poor differentiation and the presence of mutated p53
in breast cancers [53], and its nuclear staining pattern has
been reported to be correlated to tumour size [54]. A
strict correlation between HSP70 levels and increased
oestrogen receptors has also been detected [53]. Signifi-
cant increases in HSP27 and HSP70 in its inducible form
have also been observed in canine mammary tumour,
particularly in the more invasive neoplastic cells, there-
fore these proteins (and HSP90) play a meaningful role
in the multiple processes leading to malignant transfor-
mation and tumour progression in the canine mammary
gland [12]. Over-expression of the glucose-regulated
stress gene GRP78 has been observed in most of the
more aggressive ER-tumours but not in benign human
breast lesions [55].
HSP90 is a fundamental component of the steroid re-

The Role of Heat Shock Proteins in Mammary Neoplasms: A Brief Review 757
ceptor complex and is positively related to ER and
c-erbB-2 and appears to be expressed more in poorly
differentiated carcinomas [56], while a significantly de-
creased HSP90 expression has been observed in tri-
ple-negative tumours and seems not to be triggered in
precursor and pre-invasive lesions [57].
This HSP also seems to be involved in the prolifera-
tion of human breast cancer as levels of HSP90α, appear
to be positively correlated to cyclin D1 expression in this
type of tumour [20].
HSP27 cannot be considered a useful prognostic factor
in breast cancer [58] as numerous studies have produced
conflicting results. In fact, even though the positive link
with ER suggests a correlation between high levels of
HSP27 and a better prognosis, an association between
HSP27 over-expression and more aggressive tumours has
also been detected, particularly in the early stages of
breast cancer [41].
HSP27 levels have been correlated to different bio-
logical features in early and advanced breast cancer, be-
ing linked with short disease-free survival (DFS) in
node-negative patients but with prolonged survival from
first recurrence [38,45,48]. In fact high expression of
HSP27 gene has been found to be associated with in-
creased anchorage-independent growth, invasion, metas-
tasis and resistance to chemotherapeutic drugs [51,59]. A
similar correlation between HSP27 expression and tu-
mour invasiveness, in association with reduced overall
survival (OS) has also been observed in malignant canine
mammary neoplasms [12], supporting the theory that
HSP27 overexpression may influence the invasive and
metastatic potential of both canine and human breast
cancer cells [14]. It was thought that high levels of
HSP27 in advanced cancer were indicative of long sur-
vival because of the link with hormone response; how-
ever, the biological explanation for the switch from
HSP27 being a bad to good prognostic factor in early and
advanced breast cancer remains to be defined. Moreover,
HSP27 seems to sort out cases with a better prognosis
from the ER negative group of patients, with a poor
prognosis [60]. Nevertheless, subsequent other studies
have failed to detect a correlation between HSP27 ex-
pression and response to hormone therapy or with DFS
or OS [61]. High expression of Hsp 27 and HSP70 in
breast cancer correlates with lymph node involvement
[48,62-65]. The surface expression of HSPs differ-
entially regulates metastasis; murine breast carcinoma
cells sorted for high HSP25 (the murine homologue of
human HSP27) surface expression metastasized to the
lungs more aggressively than wild-type HSP25 cells
and HSP72 positive cells [6]. αß-crystallin (small HSP
family) expression is also closely tied to lymph node
involvement, and increased intensity has been correlated
to shorter survival [66]. High stress-inducible HSP70
(HSP72) expression is correlated to poor prognosis in
breast cancer [54,62,67], in particular with nuclear non-
cytoplasmatic localization [68]. This is consistent with
the association of HSP70 with some of the diagnostic
parameters of malignancy (poor differentiation, lymph
node metastasis, increased cell proliferation, block of
apoptosis, and higher clinical stage) [64]. Investigations
into the genetic polymorphism of HSP genes indicate
that homozygosity for HSP70-2 genes is significantly
associated with increased OS but not with DFS in breast
carcinoma [67,69]. HSP90 expression in breast cancer
tissues [20] and the presence of auto-antibodies to
HSP90 have been correlated with poor prognosis in
breast cancer [70,71]. In canine malignant mammary
tumours, HSP70 and HSP90 do not appear to be of sig-
nificant prognostic value but the high levels of HSP90
expression detected in neoplastic tissues, independently
of tumour histological type or aggressiveness, suggest
that this protein plays a fundamental role in malignant
transformation and tumour progression in the canine
mammary gland [12].
4. Predictive and Therapeutic Implications
of HSP Expression in Mammary Cancer
A growing body of evidence suggests that high intracel-
lular HSP27 and HSP70-family expression may render
mammary tumours resistant to a number of chemothera-
peutic agents [72,73] which is of relevance in treatment
management. However it should not be forgotten that
chemotherapeutic drugs can also induce their expression
as part of the cellular stress response, thus potentially
increasing cancer cell resistance by up-regulating anti-
apoptotic factors [74]. Although the expression of HSP27
has been correlated to ERalpha in breast cancer, its de-
tection does not predict response to Tamoxifen. Over-
expression of HSP27 has been correlated to shorter DFS
in advanced breast cancer patients who received neoad-
juvant chemotherapy [68]. In contrast, HSP70 is emerg-
ing as a predictor of resistance to chemotherapy in
breast cancer [62], but, like HSP27, it has not shown
predictive value for Tamoxifen administration [61].
Moreover, high HSP70 levels have been correlated to
lower response of breast cancers to radiation and hyper-
thermia [75].
The use of HSPs in the treatment of breast cancer
represents a new and very promising approach. Treat-
ment of tumour cells with a synthetic inhibitor of HSP27
phosphorylation [30,76], as well as knocking down using
transfection with short interference RNA [76,77], has
been found to block tumour cell migration. Many studies
have tried to establish whether HSP90-binding drugs can
effectively destabilize and reduce oestrogen receptor
levels, which are a prominent target for the treatment of

The Role of Heat Shock Proteins in Mammary Neoplasms: A Brief Review
758
hormone-dependent cancer which has become refractory
to classical hormonal therapy with anti-oestrogen agents
[21,78]. Agents such as geldanamycin (GA) or the GA
analogous 17-allylamino, 17-demethoxygeldanamycin
(17-AAG) have been shown to inhibit HSP90. 17-AAG
is an aminoquinone macrocyclic compound; it shares
the same ability of geldanamycin to bind to HSP90 and
GRP94. These drugs target the nucleotide-binding site in
the N-terminal domain of HSP90, disrupt p23 containing
HSP90 complexes preventing it from binding to client
proteins [34], like the inhibitor of apoptosis protein (IAP)
Survivin [79]. Other products such as herbimycin A,
purine-scaffold derivatives, the peptidomimetic shep-
herdin (specifically designed to block the interaction
between HSP 90 and Survivin) and the natural macrolide
radicicol inhibit HSP90 function by binding to the same
pocket [80,81]. Novobiocin, a cumarin-type antibiotic
acts in vivo and in vitro in a similar but unique manner: it
binds the C-terminal domain of HSP90 [82] and disrupts
both HSP90-HSP70-p60hop and HSP90-p50-p23 com-
plexes [83]. When GA binds to HSP90 it locks the chap-
erone in an alternative conformation that prevents normal
cycling and the formation of mature chaperone com-
plexes. The HSP90 client ER accumulates in an interme-
diate complex that recruits E3 ubiquitin ligase and drives
proteasome-mediated degradation of the protein, thereby
dramatically lowering cellular levels of the receptor and
disrupting its function (Figure 1(b)). 17-AAG has a
Figure 1. (a) Even though it is still not completely understood how HSP90 chaperone complexes recognize their substrates or
affect their conformation, a widely accepted model for a steroid hormone receptors is shown (in this case oestrogen receptor).
The current understanding of this complex indicate that generally the HSP90 complex holds the receptor (CBP: client bound
protein) in an intermediate state until the cognate hormone (L) enters the cell, but oestrogen receptor does not require con-
tinuous interaction with the Hsp90-based chaperone machinery to maintain a high affinity hormone binding conformation.
The client protein initially interacts with the “open” state of the HSP90 dimer and other co-chaperones, then, ATP binding
leads to conformational changes of HSP90, which includes the transient dimerisation of the N-terminal domains and the re-
placement of HOP by p23 and immunophillins, converting the chaperone complex into a mature state. Upon hormone bind-
ing and ATP hydrolysis, the hormone receptor is released from the HSP90 complex and the hormone is translocated into the
nucleus, where it binds specific DNA elements and activates transcription. CyP-40: cyclophilin of 40kDa; HIP: HSP70-bind-
ing cochaperone; Hop: HSP-organizing protein; (b) Inhibition of ATP binding to HSP90 prevents the formation of the ma-
ture state and results in the proteasome-dependent degradation of associated client protein. This can occur by the recruit-
ment of E3-Ubiquitin ligase, CHIP (carboxy -terminus of HSP70-interacting protein), which is a protein able to interact with
both HSP70 and HSP90. Geldanamycin and its derivatives exert their anti-tumour effect by binding to the N-terminal AT-
Pase domain of HSP90 to inhibit its chaperone function; other molecules interact with the N or C-terminal domain of HSP90
with similar effects.

The Role of Heat Shock Proteins in Mammary Neoplasms: A Brief Review 759
100-times higher affinity towards the tumour-specific
HSP90 complexed by a large number of co-chaperones
than to the HSP90 dimer, which is the predominant form
of this chaperone in normal cells [84]. However prefer-
ential GA binding has been questioned by a more recent
study that also indicated time-dependency for GA bind-
ing [85].
Chaperone-based inhibitors offer the advantage of
diminishing the level of many protein targets in parallel.
17-AAG, by simultaneously and durably inhibiting
multiple signalling activators including ErbB and Src
kinases, does not permit the re-activation of signalling
pathways by one or more redundant upstream activators
(“oncogene switching”) and results in a more prolonged
and robust inhibition of downstream signalling path-
ways in breast cancer cells than do individual tyrosine
kinase inhibitors, such as gefitinib, which appear to lose
the ability to modulate ErbB-driven signalling pathways
over time [86]. It has also proved of use in the treatment
of trastuzumab-resistant ErbB2-overexpressing tumours
[87]. The anti-pro-liferative effect of 17-AAG posi-
tively correlated with phosphorylation and downregula-
tion of ErbB2 with a marked increase in apoptosis, al-
though, necrosis was also present especially at higher
doses [88]. A second more soluble and less hepatotoxic
generation analogue of GA is 17-(dimethylaminoethy-
lamino)-17-demethoxygeldanamycin (17-DMAG) [89].
In vivo and in vitro, 17-DMAG exerts anti-angiogenic
activity interfering with HSP90 chaperone performance
on VEGF induced expression in endothelial cells, and
regulating HIF-1α activation [90]. Clinical development
of the geldanamycin derivatives 17-AAG and 17-DMAG
was discontinued some time ago [15,91-97]. In phase I
trials, 17-DMAG [98,99] exhibited an unfavourable
toxicity profile. Clinical trials have been done with an
optimized 17-AAG formulation KOS-953 (Tanespimy-
cin) being used alone and in combination with other
chemotherapeutic agents [100]. The wide array of HSP90
inhibitors and their clinical applications have been re-
viewed extensively elsewhere [97,101-106], and a sum-
mary of trials currently in progress provided by the US
National Cancer Institute is available at the web page
http://clinicaltrials.gov/ct2/results?term=hsp90+inhibito
r&pg=1.
It would appear that combination therapies, using low
doses of HSP90 inhibitors together with conventional
chemotherapeutic agents (such as Taxol), are an effective
means of targeting some cancers [96,107-116]. How-
ever at this stage it is difficult to predict which patients
could benefit from anti HSP90 therapy. In vivo testing of
HSP90-targeted cancer therapy is essential as potential
contraindications have arisen: 17-AAG appears to en-
hance bone metastasis of a human breast cancer cell line
following intracardiac inoculation in the nude mouse
[117] and paradoxically it may also cause the transcript-
tional activation of HSF-1 by disrupting HSP/HSF-1
complexes and thus an increase in the overall amounts of
HSP 40, HSP70 and HSP90 [35].
Small synthetic HSP90 inhibitors based on a purine
scaffold have been developed which interact with the
N-terminal ATP pocket, and produce biological effects
similar to geldanamycin. Some of them are under ad-
vanced preclinical investigation and CNF-2024, a 9-
benzyl purine derivative, has entered Phase I clinical
trials in advanced breast cancer [118].
Another novel small-molecule inhibitor of HSP90 based
on the 4,5-diarylisoxazole scaffold (NVP-AUY922) in-
hibits HSP90 in vitro and exhibits potent anti-tumour
activity at tolerated doses in an ER- and ErbB2-posi-
tive human breast cancer model [119]. A summary of
the HSP90 inhibitors clinical trials currently in prog-
ress is provided by the US National Cancer Institute
(http://clinicaltrials.gov/ct2/results?term=hsp90+inhibitor
&pg=1).
A different approach to inhibiting HSP90 function is
disrupting its interaction with co-chaperones, such as
HOP (HSP organizing protein) [120] or AHA1 (activator
of HSP90 ATPase) [121].
Treatment of human breast cancer cell lines with these
compounds results in a drop in—the levels of the HSP90-
dependent client protein HER2, or in an increase in sen-
sitivity to 17-AAG with consequent cell death. Treatment
with hydroxamic acid analogue pan-HDAC inhibitors
(HA-HDI) induces HSP90 hyperacetylation, this inhibits
its chaperone function decreasing its binding to ERalpha,
and sensitizes ERalpha-positive breast cancer cells to Ta-
moxifen [122]. Inhibition of cell-surface HSP90 with
antibodies or cell-impermeable HSP90 inhibitors blocks
cell motility and invasion in vitro and cancer metastasis
in vivo [123].
HSF-1, HSP27, HSP70, and GRP78 are also the tar-
gets of antisense oligonucleotide therapies [10]. All ele-
ments of the HSF-1 activation and down regulation cas-
cade and Ralbinding protein 1, tubulin and p23 are of
great interest as potential drug targets [35]. Chemical
inhibitors of HSF-1 activation (genistein, KNK437 and
Triptolide) are in a very early stage of development but
their effective- ness in breast cancer treatment has yet to
be proven [106,124].
When located in the extracellular space or on the
plasma membrane, HSPs may provide a target for im-
munotherapy protocols because they are able to chaper-
one tumour antigens and act as biological adjuvants to
break immune tolerance to tumour antigens causing tu-
mour regression [125,126]. The immunoregulatory func-
tions of HSPs are represented by the ability of such
chaperones to bind to several tumour-associated pep-
tides/proteins. These complexes can be recognized by

The Role of Heat Shock Proteins in Mammary Neoplasms: A Brief Review
760
specific receptors on the surfaces of antigen presenting
cells confirmed to be CD40 or CD91 (also known as
a2-macroglobulin receptors which act as global receptors
for HSPs) and cell processed. The purpose is to elicit a
specific immune response against its own tumour using
tumour-derived HSPs (mainly gp96, HSP70, HSP90 and
calreticulin) covalently binding to specific tumour pep-
tides—i.e. tumour antigen mucin (MUC1) derived pep-
tides [127]—as natural adjuvants that present to the im-
mune system the molecules that have shielded the poten-
tial epitopes from immune recognition [30,128]. Pre-
clinical studies have been conducted to design a variety
of novel HSP-based tumour vaccines with improved
therapeutic potential: a reproducible anti-tumour re-
sponse has been reported in approximately 50% of sub-
jects studied [129,130]. These approaches include de-
velopment of HSP fusion proteins and genetic vaccines
using plasmid DNA and adenoviruses [126]. This topic
has been reviewed in detail [126,131,132]. Studies have
demonstrated that such active-specific immunotherapy
has potential for controlling mammary tumour progress-
sion. BALB/c female mice vaccinated with a repeat
beta-hCG C-terminal peptide carried by mycobacterial
HSP65 induced high avidity antibodyies and effectively
inhibited the growth of EMT6 mammary tumour cells
injected subcutaneously [125]. Smith et al. (2008) [130]
have recently demonstrated that perioperative vaccina-
tion with an ex vivo HSP-loaded dendritic cell vaccine
abrogated recurrent tumour growth in an in vivo model of
breast-conserving surgery for breast cancer (BALB/c
mice).
Finally, the differing expression of HSPs in mammary
carcinomas and conflicting results may be the result of
the complex array of genetic (derepression/repression of
specific genes) and epigenetic (methylation of genes)
alterations that characterizes the process of carcinogene-
sis and its intrinsic genetic instability. Recent studies
have implicated HSP90 in transcriptional regulation de-
monstrating an important role for it in buffering genetic
and epigenetic variation leading to altered phenol-types.
It cooperates with Trithorax (a TrxG chromatin protein)
maintaining the active expression state of targets like the
Hox genes [133]. Aberrant expression of Hox genes is
related to the development of breast cancer and the ma-
lignant behaviour of cancer cells, and the expression of
HoxC5 is lower in cancerous tissues with mutated-type
p53 than in normal and cancerous tissues with wild-type
p53 [134,135]. Pharmacological inhibition of HSP90
results in degradation of Trx and a concomitant down-
regulation of homeotic gene expression [133].
5. Conclusions
Studies on this subject clearly indicate that intracellular
and extracellular HSPs play a significant role in the bio-
logical and clinical aspects of mammary cancer. Al-
though of no particular significance on a diagnostic level,
HSP27 and HSP70 are, however, useful biomarkers for
carcinogenesis and can predict response to some anti-
cancer therapies. HSP90, on the other hand, represents a
promising target for the treatment of breast cancer. Major
advances have been made in recent years in understand-
ing the complex structural and functional relationship
between HSPs and their co-chaperones, and identifying
client proteins in breast cancer.
Currently the potential of HSP90 inhibitors, that have
proven to be effective in killing cancer cells, lies in pro-
longed disease stabilization. Further study will help iden-
tify novel HSP90 N- terminal-ATPase inhibitors or more
sophisticated drugs capable of taking advantage of the
immunogenic properties of extracellular HSPs.
6. Acknowledgements
We would like to thank Tania Bastow for the linguistic
review of the manuscript.
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