INTRODUCTION
Breast cancer is the most common female cancer globally, representing
nearly a quarter (25%) of all cancers. Organic carcinogens covalently
bind DNA formingstable and depurinating adducts. The compound
4-hydroxyestradiol and estradiol-3, 4-quinone (E1(E2)-3,4-Q)) produces
significantly higher levels of depurinating adduct and smaller stable
adduct (1). These estrogen-DNA adducts are quickly lost by the cleavage
of the glycosyl bond from DNA and create apurinic sites that can cause
cancer (2,3). Mounting evidences demonstrate that a few E2 metabolites
(i.e. CE-3, 4-Q) interact with DNA and form 4-OHE1(E2)−1-N3Ade and
4-OHE1(E2)-1-N7Gua that causes DNA mutation and potential cellular
transformation (4,5).
The use of human breast epithelial cell lines such as MCF-10F, an
immortalized, non-transformed estrogen receptor (ER)-α-negative cell
line has identified the initiation of cancer by estrogen-DNA adducts.
Results indicate that beside the alteration of E2-ER signaling,
genotoxic effects via estrogen metabolite are partly responsible for the
malignant transition . These findings support the hypothesis that the
availability of the active estrogen is a critical determinant in the
treatment of some breast cancer.
A large percentage of breast cancers are sensitive to estrogen and have
a good response to endocrine therapy based on selective ER modulators
(SERM) i.e. tamoxifen (7) and fulvestrant (8). Reduction in estrogen
synthesis by aromatase-inhibitors of is also a vital strategy (9).
Beyond these strategies, estrogen metabolizing enzymes are given less
priority for research. SULT1E1, a phase II metabolizing enzyme that is
located in the cytoplasm and responsible for sulfonation of estrogen
(10). SULT1E1 polymorphisms are shown to be a risk factor for breast and
endometrial cancers, (11) suggesting that its modulation might be an
attractive strategy in the prevention, management and or treatment of
breast cancer. In contrary, the steroid sulfatases (STs) converts water
soluble sulfated-estrogen to insoluble estrogen in the target tissues.
Roughly, it sketches that activation of SULT1E1 and inhibition of STS
might work in favor of breast cancer treatment.
The induction of SULT1E1 along with anti-breast cancer action of TM208
and tamoxifen (ER antagonist) may bring better treatment outcomes in
hormone ER+ breast cancers. Estrogen is differentially metabolized in
healthy ovarian surface epithelium (OSE) and in epithelial ovarian
cancer (EOC) cells. Total mRNA assay by qRT-PCR revealed significantly
higher SULT1E1 mRNA expression in OSE than in EOC. Inflammatory
cytokines further augmented the local production of E2 by stimulating
STS and suppressing SULT1E1 (12). It was concluded that the local
estrogen metabolism may be a target for EOC treatment. SULT1E1 is
transcriptionaly regulated under oxidative stress, and is also a target
of NRF2. Oxidative stress responses augment Nrf-2 and HIF-1a in breast
cancer cell. Hypoxia Inducing Factor (HIF) target genes in every step of
the metastatic process. Digoxin which blocks HIF action eventually
decreases primary tumor growth, vascularization and invasive metastasis
in animal models of breast cancer (13,14). Degeneration of extracellular
matrix is implicated as the metastatic growth factor and MMPs are highly
expressed in advanced breast cancer. A high expression of MMP-2 and
MMP-9 was found in >75% of breast cancer patients (15).
So, it is suggested that the restriction in HIF1α and MMP activities may
have therapeutic prospects against breast cancer.
In our earlier study, we explored that the pre-tumorigenic condition
induced by ethylnitrosourea (ENU) and E2 showed impairment of SULT1E1
expression and E2 regulations via oxidant-stress signaling (16). Thus,
induction and activation of SULT1E1 might become cancer prevention and
treatment startegy. An earlier study demonstrated that dialylsulfide
(DAS) treatment caused the nuclear accumulation of constitutive
androstane receptor (CAR) resulting in a significant increase of SULT1E1
mRNA and protein in the liver of female mice. DAS effectively reduces
lipid peroxidation, recovering cell viability, attenuating DNA strand
breaks in cultured breast cancer MCF-10A cells (17). Despite of
significant SULT1E1 induction by DAS, the endogenous E2 level was
unaltered and no increase in estrone sulfate level was noticed.
Contrarily, the clearance of exogenously administrated E2 was
accelerated in DAS treated mice (18). This suggests that under variable
oxidative stress condition, SULT1E1 transits between gain and loss of
enzyme activity Our previous report suggests that oxidative stress
induced SULT1E1 modifications may be similar in human breast cancer
tissue and experimental animal model (16). Further study demonstrates
that transcriptional regulation of stress, promotes Nrf-2 and
proinflammatory marker NFkβ through E2 mediated signaling. These
signallings are also associated with breast cancer initiation and
severity. So, a reducing environment is required to keep SULT1E1 active
which may keep E2 levels under control, SULT1A1 also sulfoconjuagtes E2
but at higher concentration and definitely contributes to control the E2
pool. Chalcone posses oxidative stress relieving property and and act as
antioxidant in different diseases (19). Hence, we opted for Chalcone in
this study to induce cellular reducing environment to keep SULT1E1
active together with Dialylsulfide that induces mRNA/protein expression
of SULT1E1. Our present study may have some therapeutic implications in
breast cancers.