Trial Information

Dietary Seaweed and Early Breast Cancer: A Randomized Trial

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).