Breast Cancer Invasion and Metastasis
Experimental Metastasis: Modeling and Analysis
Estrogen disrupting chemicals are environmental compounds which mimic, antagonize or interfere in the action of physiological estrogens. They occur naturally (plant phytoestrogens) but the majority are man-made compounds, which, through their use in agricultural, industrial and consumer products, have become widely present in human tissues including breast tissue. Since exposure to estrogen is a risk factor for breast cancer, estrogen disrupting chemicals may also contribute to breast cancer
... to breast cancer development. This review discusses evidence implicating estrogen disrupting chemicals in increasing migratory and invasive activity of breast epithelial cells, in epithelial-tomesenchymal transition, and in growth of breast tumours at metastatic sites as well as the primary site. Mechanisms may be through the ability of such chemicals to bind to estrogen receptors, but unlike for proliferation, effects on cell migration and invasion are not limited to estrogen receptor-mediated mechanisms. Furthermore, whilst effects on proliferation can be measured within hours/days of adding an estrogen disrupting chemical to estrogen-responsive breast cancer cells, effects on cell migration occur after longer times (weeks). Most studies have focused on individual chemicals, but there is now a need to consider the environmentally relevant effects of long-term, lowdose exposure to complex mixtures of estrogen disrupting chemicals on mechanisms of metastasis. ENDOGENOUS ESTROGENS AND METASTASIS Cellular actions of estrogens are mediated through binding to specific receptor proteins  . There are two types of nuclear estrogen receptors, estrogen receptor a (ERa) and estrogen receptor b (ERb) which exist as multiple isoforms and which function as ligand-activated transcription factors to influence patterns of gene expression  . Final outcomes are dependent on the affinity of ligand binding to receptor, the concentrations of receptors in the target cells and the presence of co-acting factors/transcription factors  . In addition, estrogenic ligands can also act through binding to membrane-associated molecules such as the G-proteincoupled estrogen receptors [8, 9] . Metastasis involves a complex series of events whereby the malignant cells break away from the primary tumour, invade through local tissue, infiltrate circulatory vessels (blood and/or lymph) and at distant sites exit the vessels to from new foci of cancer cell growths (colonization)  . Endogenous estrogens can influence all these processes including immune evasion and the angiogenesis needed for effective metastatic colonization  . In their capacity to regulate growth of estrogen-responsive human breast cancer cells [2, 4] , estrogens can influence metastatic tumour growth at both the primary and secondary sites  .