Dietary Seaweed and Early Breast Cancer: A Randomized Trial
Condition: Seaweed Associated Changes in Healthy Subjects
Study type: Interventional

Summary: 
      Could daily consumption of seaweed help explain lower postmenopausal breast cancer (BC)
      incidence and mortality rates in Japan? This small proof of principle clinical trial was
      designed to test the idea that the same amount of seaweed normally eaten in Japan would
      induce metabolic changes when given to non-seaweed consuming healthy postmenopausal American
      women. The participants were given 10 capsules a day (about 1 tablespoon) for 3 months.
      During the first month the capsules contained placebo, the second month seaweed, and the
      third month placebo. We collected blood and urine samples after each treatment period and
      tested for changes in protein expression that might be related to consuming seaweed.
    

Detailed description: 
      The relationship between the relative breast cancer (BC) risk and seaweed intake among humans
      is only now unfolding. A small body of research, both in vivo and in vitro, suggests seaweed
      may be useful in BC prevention (Funahashi et al. 1999; Teas et al. 1984; Yamamoto et al.
      1987) . Seaweeds are specifically used to treat tumors in Traditional Chinese Medicine and
      Japanese folk medicine. On a population level, those people for whom seaweed is a regular
      part of their diet, most notably in Japan, have dramatically lower rates of BC (Hebert et al.
      1998; Hebert and Rosen 1996; Kodama et al. 1991).

      Epidemiologic studies done in Japan in the 1980s, before Westernized diets were common,
      reported that Japanese women had 1/3 the rate of premenopausal BC and 1/9 the rate of
      postmenopausal BC (Ferlay et al. 2001; Reddy et al. 1980). Even today, BC incidence rates for
      women in Japan are 20/100,000 compared to the U.S. average of 118/100,000 (Statistics 2007) .
      Although genetic predisposition has been proposed, when rates among migrants from Japan to
      the US are compared, BC incidence almost doubles after 10 years of residence in the US
      (20/100,000 to 35/100,000) (Shimizu et al. 1991), increase with each successive generation
      (LeMarchand et al. 1985). Japanese-American women who develop BC have significantly better
      survival rates than other American ethnic groups (Kanemori and Prygrocki 2005; Pineda et al.
      2001). On the other hand, Asian-American women over 50 years of age living in Los Angeles,
      especially Japanese-American women, have one of the most rapidly increasing BC incidence
      rates (Deapen et al. 2002). These data support the hypothesis that lifestyle changes and
      possibly gene-nutrient interactions are important in BC susceptibility.

      Seaweed is a typical part of East-Asian diets, although consumption varies widely among
      individuals (Fukuda et al. 2007). Seaweeds have no land equivalents in terms of their
      specific components of fiber (alginate), primary carotenoid (fucoxanthin), sulfated
      polysaccharide (fucoidan and laminarin), and polyphenol defense compounds, each of which has
      been reported to have strong anti-cancer activity (Kotake-Nara et al. 2005; Koyanagi et al.
      2003; Miao et al. 1999; Son et al. 2003).

      Many in vivo and in vitro studies of dietary seaweed report decreased angiogenesis and
      increased apoptosis of tumor cells (Konishi et al. 2006; Koyanagi et al. 2003; Sekiya et al.
      2005), inhibition of tumor cell adhesion and metastasis (Liu et al. 2005) and enhanced immune
      responses (Maruyama et al. 2003; Maruyama et al. 2006). Nishino and colleagues have
      investigated seaweed modulation of the urokinase plasminogen system (Nishino et al. 1999;
      Nishino et al. 2000). Based on the wide range of antitumor effects, we investigated the
      possibility that seaweed could affect uPAR concentrations in women who consume seaweed. The
      urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor
      (uPAR, CD87), and its plasminogen inhibitors 1 and 2 are central to the maintenance of
      homeostasis, directly affecting the extracellular matrix (ECM), inflammation, tissue repair.
      Increased concentrations have been shown to be associated with more rapid cancer progression
      (Foekens et al. 2000). Urinary concentration of uPAR is highly correlated with urinary uPA
      concentrations, and both are correlated with tissue concentration (Foekens et al. 2000; Sier
      et al. 2004).When uPA/uPAR concentrations are increased, there is increased ECM degradation
      that allows cancer cells to migrate, leading to metastases. Urokinase is also used
      therapeutically to treat serious conditions involving blood clots. In clinical studies,
      tissue concentration of uPA is an independent prognostic predictor of BC progression
      (Ceccarelli et al. 2010; Look et al. 2002).

      We therefore included evaluation of one part of the urokinase system, uPAR, in this study as
      a possible biomarker for seaweed activity that might be related to BC prevention.

      To further assess whether a dietary seaweed intervention could alter protein expression in
      urine and serum in a non-seaweed consuming population of healthy postmenopausal women, we
      used surface enhanced laser desorption/ionization time of flight coupled with mass
      spectrometer (SELDI-TOF-MS). Proteomic analyses have been used to identify cancer biomarkers
      with high sensitivity and specificity, including those related to BC (Gast et al. 2008;
      Shimizu et al. 1991; van Winden et al. 2009). SELDI has also been shown to be sensitive
      enough to be used to identify changes in serum associated with the addition of a novel food
      (green tea) (Tsuneki et al. 2004).
    

Intervention name(s): Seaweed; Placebo; Placebo2
Intervention type(s): Other; Other; Other
Intervention description(s): Ten 500-mg capsules to be taken orally each day for 1 month; Ten 500-mg capsules to be taken orally each day for 1 month; Ten 500-mg capsules to be taken orally each day for 1 month
Other intervention name(s): Undaria pinnatifida; Maltodextrin; Maltodextrin
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: urokinase receptor; protein expression; seaweed (Undaria pinnatifida)