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Page 8 of 13 Darbre. J Cancer Metastasis Treat 2019;5:58 I http://dx.doi.org/10.20517/2394-4722.2019.22

rainwater into rivers and lakes and then pass up the food chain dissolved in animal fat. They are measured
[64]
ubiquitously in human tissues . There are 75 congeners of which the most toxic is 2,3,7,8-tetrachlorodi
[64]
benzodioxin (TCDD) and has been shown to exert molecular actions both through ER-mediated and
[66]
AhR-mediated mechanisms . Gene targets of the AhR include activation of slug and some MMPs . In
[65]
the ER+, AhR+ MCF-7 human breast cancer cells, TCDD has been found to downregulate E-cadherin and
reduce cell-cell contacts in a JNK-dependent mechanism . However, antiestrogenic actions of TCDD have
[67]
[65]
been repeatedly reported over the years , and so it is noteworthy that TCDD has been reported to inhibit
mammary tumour metastasis in vivo [68,69] .
Phytoestrogens
Phytoestrogens are found in over 300 plant species and can be ingested by humans through consumption
[70]
of plant material either in diet or as dietary supplements . Flavonoids include genistein and daidzein
found in soybeans and other legumes, coumestans in clover and young sprouting legumes, prenylflavonoids
in hops. The most prevalent non flavonoids are lignans in cereals, fruits and vegetables. Although many
purified phytoestrogens display estrogenic activity in vitro, the estrogenic actions on cell proliferation are
concentration-dependent with only the lower doses increasing proliferation of estrogen-responsive human
[71]
breast cancer cells, whilst higher doses inhibit , and many phytoestrogen-containing plant products are
considered to have anti-tumour activity . It is interesting therefore that emerging data seem to suggest
[70]
[72]
that several phytoestrogens can act to reduce breast cancer cell migration and invasion including lignans ,
[47]
soy-derived daidzein , and formononetin . Triclosan-induced EMT can be reversed by kaempferol .
[74]
[73]
However, one mouse model of breast cancer has shown that consumption of soy isoflavones increased
[75]
growth of metastatic tumours in bone and lung .
THE ISSUE OF LOW-DOSE MIXTURES
The studies discussed above provide evidence that some individual estrogen disrupting chemicals can
influence components of EMT and processes of migration and invasion in human breast cancer cells.
However, since many hundreds of estrogen disrupting chemicals have now been measured in the human
[1]
breast , the environmental reality is that, in today’s world, human breast cells in vivo are not exposed
to single chemicals but to complex mixtures of pollutant chemicals. This is especially poignant in view
of many estrogen disrupting chemicals being lipophilic and the human breast being a fatty organ. It is
also highly relevant in the context of the many non-monotonic responses which have been reported for
environmental endocrine disrupting chemicals in general, often with stronger responses at the relatively
[76]
lower doses tested . There are therefore outstanding questions as to the effects of exposure to complex
mixtures of estrogen disrupting chemicals where each is present at low dose. For proliferation, it has been
shown that mixtures of such chemicals can increase cell proliferation where the same concentrations of
the estrogen disrupting chemicals individually do not, in what has now been nicknamed “the something
from nothing” effect . Even mixtures of the different esters of parabens can add together to give increased
[77]
[29]
cell proliferation . This is relevant environmentally where human breast tissue samples were found to
[26]
contain differing levels of the individual paraben esters and implies that the same outcomes can arise
[29]
from different mixtures of estrogen disrupting chemicals . Clearly in ER-mediated mechanisms, such as
in increasing cell proliferation, each chemical will act according to its relative estrogen receptor binding
affinity but low doses of different chemicals can add together until a maximum proliferative signal is
achieved. As yet, there seems to be no published information as to whether the same effect of mixtures can
be achieved on development of EMT or on increasing cell migration/invasion. Furthermore, since these
studies are technically long and labour-intensive, the range of concentrations are often lacking in order to
determine the extent to which non-monotonic responses may be occurring.