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        <article-title>Submitted manuscript to Archives of Breast Cancer; PEER review version Waterpipe Smoking and Breast Cancer Risk: The Emerging Need for Research and Prevention</article-title>
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      <p>increasing rates and unequitable resources 2 .</p>
      <p>Tobacco smoke is the most important human carcinogen and passive and active smoking is among the known risk factors of breast cancer <xref rid="b1" ref-type="bibr">1</xref> . Although consistent evidence exists for a moderate increase in the risk of breast cancer in women who smoke tobacco <xref rid="b2" ref-type="bibr">2</xref><xref rid="b3" ref-type="bibr">3</xref> , much less is known about potential association between waterpipe smoking and breast cancer risk. Waterpipe (also known as hookah, hubble­bubble, narghile, shisha, borry or goza) is a form of tobacco consumption that the smoke bubbles through water before reaching the smoker.</p>
      <p>The highest rates of waterpipe use have been reported from the Middle East, Asia and Africa, but it has rapidly become an emerging problem in the United States as well as Europe <xref rid="b4" ref-type="bibr">4</xref> . The reasons for increasing popularity include misconceptions about safety (in comparison to cigarette smoking) as the smoke passes through water, introduction of flavoured tobacco, social acceptability and lack of waterpipe­specific control policy and regulations <xref rid="b5" ref-type="bibr">5</xref><xref rid="b6" ref-type="bibr">6</xref> . Women and young people seem more likely to be choosing waterpipe over cigarettes, with the prevalence surpassing cigarette smoking in some areas <xref rid="b6" ref-type="bibr">6</xref> . These studies are alarming and call for an urgent need for increasing awareness among women and promoting research in this area.  </p>
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      <title>References</title>
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          <title>waterpipe smoking session lasts about 45 minutes to one hour, exposing the active and passive smokers to tobacco­specific nitrosamines, polycyclic aromatic hydrocarbons, volatile aldehydes, nitric oxide and heavy metals3 . A naturalistic study (in a bar setting) among 55 water pipe smokers (43.6% female) demonstrated 73­fold increase in urine nicotine and 2­fold increase in tobacco­specific nitrosamine (NNAL) immediately following waterpipe smoking9 .Although the impact of these alarming trends are not yet reflected in breast cancer risk, there are some in vitro studies supporting this association. Waterpipe smoke has been shown to induce epithelial-mesenchymal transition (EMT) of MCF7 and BT20 breast cancer cell lines and enhances cell invasion ability of both cell lines in comparison with their matched controls. In addition, waterpipe smoke provokes a down­ and up­regulation of E­cadherin and focal adhesion kinase (FAK), respectively, which are important regulators of cancer progression genes. It also incites the activation of Erk1/Erk2, which could be the underlying mechanism for stimulating epithelial-mesenchymal transition and enhancing invasion as well as the deregulation of E­ cadherin and FAK expression10 .</title>
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          <title>Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians. 2021.2.Karbakhsh M. Global Breast Cancer Initiative: an Integrative Approach to Thinking</title>
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