SKBR3 cells (B) and MCF-7 cells (C) were seeded in six-well plates and treated for 48 h as described above. differentiation. Finally, exogenous AhR agonists were able to promote differentiation inside a putative mammary malignancy stem cell collection. Cumulatively, these results suggest that the AhR takes on an important part in mammary epithelial differentiation and, as such, represent a encouraging restorative target for a range of phenotypically unique human breast cancers. The AhR inhibits invasive properties and promotes differentiation of breast malignancy cells; thus, the receptor represents a encouraging therapeutic target for human breast cancers. Breast malignancy is currently the most prevalent malignancy among women in industrialized countries and comprises 30% of all cancers found in women. The statistics indicate that one in eight women will develop breast malignancy at some point in her lifetime, and nearly 200,000 women will be diagnosed with breast cancer in the United States each year (1,2). For metastatic breast cancer specifically, it is estimated that nearly 155, 000 women in the United States are currently living with the disease, and this number is expected to increase by 5% over the next several years (3). Despite the availability of adjuvant therapies targeting estrogen and growth factor-signaling pathways, the incidence and mortality of breast cancer have not declined at the same rate as other major causes of death, which highlights the need for new therapeutic targets and treatment modalities. The aryl-hydrocarbon receptor (AhR) was initially recognized in early toxicology studies that observed an increase in mono-oxygenase activity after exposure to polyaromatic hydrocarbons. Genetic and biochemical studies mapped the response to a single autosomal locus and led the eventual cloning of the AhR (4,5,6,7). Molecular characterization of the AhR across vertebrate and invertebrate species demonstrated that this receptor is highly conserved (8) and plays a significant role in tissue development (9,10,11,12,13). In the mouse, for instance, targeted disruption of the AhR results in altered immune function (14), ovarian follicle development (15), seminal vesicle maintenance (16), vascular remodeling (17), and mammary development (18). The cancer-related effects of AhR activation have been primarily characterized using xenobiotic ligands. Similar to the nuclear hormone receptors, these studies have identified context- and tissue-specific effects that include tumor promotion in certain tissues and a decreased tumor incidence in others. In occupational exposures to the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), workers had an increased risk for all those combined cancers and for lung malignancy (19). A separate epidemiological study of a population RepSox (SJN 2511) exposed to TCDD after an industrial accident found a significant decrease in breast and endometrial cancers (20). More recently, a report following a population exposed to dioxin emissions from a municipal waste incinerator noted a significant decrease in incidence of invasive breast cancer in women living in the highest exposed zone (21). The Goserelin Acetate tissue-related differences in the tumor response in humans were also observed in rodent studies. In a recent comprehensive rodent malignancy bioassay study, an increased tumor incidence was observed in the liver, lung, and oral mucosa, whereas a significant decrease in tumors was observed in the mammary gland, pituitary, and thyroid (22). A reduction in 7,12-dimethylbenz[a]anthracene-induced mammary tumors has also been observed after treatment with TCDD (23). Mechanistic studies on the protective effects of AhR agonists in breast cancer have indicated that this receptor is engaged in the regulation of several unique processes. It has been demonstrated that this protective effects of AhR ligands on tumor growth are related to the ability of the receptor to antagonize estrogen receptor (ER) signaling (24,25,26,27,28). The functional consequences of the antagonistic AhR-ER cross talk are apparent in bothin vitroandin vivomodels RepSox (SJN 2511) in which TCDD was shown to completely reverse the proliferative effects of estrogens (29,30). RepSox (SJN 2511) In addition to the antagonistic effects on ER signaling, the AhR also regulates important processes required for breast malignancy cell growth, cell cycle control, chemokine signaling, and cell migration (31). Previous studies have exhibited that TCDD can down-regulate both CXCR4 and CXCL12 in a breast cancer cell collection and decrease cell migration toward a CXCL12 gradient (32). The initial identification of the AhR as the receptor for polyaromatic hydrocarbons has contributed to its perceived role as a xenobiotic sensor..