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Editorial
Open Access
The Prevalence of Anaemia among Reproductive Age Group (15-45 Yrs)
Women in A PHC of Rural Field Practice Area of MM Medical College,
Ambala, India
Yasunari Kanda
Division of Pharmacology, National Institute of Health Sciences, Setagaya 158-8501, Japan
*Corresponding author:
Yasunari Kanda
Division of Pharmacology
National Institute
of Health Sciences
1-18-1, Kamiyoga
Setagaya, Tokyo 158-8501, Japan Tel: +81-3-3700-9704 Fax: 81-3-3700-9704 E-mail: kanda@nih.go.jp
Received July 18, 2012; Accepted July 18, 2012; Published July 20, 2012
Citation: Kanda Y (2012) Cigarette Smoke and Breast Cancer Stem Cells. J
Women’s Health Care 1:e104. doi:10.4172/2167-0420.1000e104
Epidemiological studies have suggested that cigarette smoking is
related to increased breast cancer risk. In agreement with this, clinical
studies indicated that smoking increases breast cancer mortality and
the incidence of metastasis from the breasts to the lungs [1,2]. Cigarette
smoke contains over 4000 different chemicals, many of which are toxic
and carcinogenic in a variety of cells, including breast epithelial cells [3].
Among them, nicotine is considered to be related to increased cancer
risk. For example, nicotine has been shown to induce resistance to the
chemotherapeutic drug doxorubicin in human MCF-7 breast cancer
cells [4]. Moreover, this compound has been shown to release vascular
endothelial growth factor, which plays a key role in angiogenesis [5].
However, limited experimental data support direct links between
breast cancer and nicotine exposure. In addition, the mechanisms by
which nicotine might promote breast cancer are not fully understood.
Growing evidence suggests that tumors are organized in a hierarchy
of heterogeneous cell populations and are formed and maintained by a
small population of stem/stem-like cells known as “Cancer Stem Cells
(CSCs)” [6]. CSCs show the following characteristics: self-renewal,
drug resistance, and high tumorigenicity. Only genetic mutationinduced
CSCs have the ability to form tumors. Because CSCs share
many molecular similarities with embryonic and tissue stem cells,
all the major signaling pathways such as Notch, Wnt, and Hedgehog
involved in normal stem cell biology have been implicated in CSC
proliferation [7-9].
Aldehyde dehydrogenase (ALDH), a detoxifying enzyme
responsible for the oxidation of intracellular aldehydes, is a functional
marker for breast CSCs, and its expression is correlated with poor
prognosis, increased metastasis, and chemotherapy resistance in breast
cancer patients [10-12]. However, the relationship between cigarette
smoke and CSCs has not yet been elucidated.
Hirata et al. [13] have recently showed that nicotine induces breast
CSC proliferation by binding to their nicotinic acetylcholine receptors
(nAChRs) x. Nicotine concentrations comparable to those reported
in the plasma of cigarette smokers increased both the frequency and
absolute number of CSCs, which were identified as ALDH-positive
MCF-7 cells. Furthermore, nicotine-induced CSC proliferation is
blocked by N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine
t-butyl ester (DAPT), which prevents Notch signaling by inhibiting
cleavage of the activated Notch receptor by γ-secretase, suggesting
a possible role of Notch in breast CSC biology. The involvement of
Notch signaling has been well characterized in breast cancer. Aberrant
Notch activation has been reported in various subtypes of breast
carcinoma [14], and a recent study showed that the co-expression
of Notch-1 and one of its ligands, jagged-1, correlated with poor
prognosis [15]. Interestingly, another study has shown that exposure
to cigarette smoke extracts activated Wnt and Hedgehog pathways in
bronchial epithelial cells [16]. Taken together, these data suggest that
cigarette smoking could activate signaling pathways involved in stem
cell proliferation. More specifically, it is possible to hypothesize that
nicotine-mediated breast CSC proliferation via the Notch pathway
might be involved in the progression of breast cancer. The mechanisms
underlying the nicotine-mediated stem cell pathway activation remain
to be determined. In addition, in vivo studies are required to elucidate
the effects of nicotine on breast CSCs.
The α7 subtype of the nAChR has been identified as the major mediator of breast CSC proliferation [13]. Moreover, nAChR is
overexpressed in breast cancer [17]. It is possible, therefore, that
nicotine could stimulate breast CSCs growth via this receptor. Because
targeting nAChR is considered highly selective for cancer cells, nAChR
might be a good target for cancer treatment. In agreement with this,
recent studies have shown that, nAChR antagonists are promising
agents for the treatment of lung cancer [18]. However, because nAChR
is widely expressed in various stem cells [19], the risks of unexpected
side effects must be carefully assessed.
In addition to nicotine, the nicotine-derived nitrosamine ketone
(NNK), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, acts as an
agonist to nAChR with higher affinity for α7-nAChR than nicotine
and has been found to transform normal human breast cells [20].
Therefore, NNK is also a potential inducer of breast CSC proliferation.
Future studies are required to examine which of the 4000 components
in cigarette smoke are responsible for breast CSC proliferation and
cancer progression.
In conclusion, growing evidence suggests that nicotine in cigarette
smoke plays a key role in breast cancer. In particular, the finding that
nAChR regulates breast CSCs and provides important insights into
the relationship between cigarette smoking and breast cancer. The
development of agents that disrupt the nAChR signaling pathway may
provide a new therapeutic approach for the treatment of breast cancer.
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