The cooked meat-derived mammary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) elicits estrogenic-like microRNA responses in breast cancer cells.

The cooking of meat results in the generation of heterocyclic amines (HCA), the most abundant of which is 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Data from epidemiological, mechanistic, and animal studies indicate that PhIP could be causally linked to breast cancer incidence. Besides the established DNA damaging and mutagenic activities of PhIP, the chemical is reported to have oestrogenic activity that could contribute to its tissue specific carcinogenicity. In this study we investigated the effect of treatment with PhIP and 17-ß-estradiol (E2) on global microRNA (miRNA) expression of the oestrogen responsive MCF-7 human breast adenocarcinoma cell line. PhIP and E2 caused widespread and largely over-lapping effects on miRNA expression, with many of the commonly affected miRNA reported to be regulated by oestrogen and have been implicated in the initiation and progression of breast cancer. The regulatory activity of the miRNAs we show here to be responsive to PhIP treatment, are also predicted to mediate cellular phenotypes that are associated with PhIP exposure. Consequently, this study offers further support to the ability of PhIP to induce widespread effects via activation of oestrogen receptor alpha (ERα). Moreover, this study indicates that deregulation of miRNA by PhIP could potentially be an important non-DNA-damaging carcinogenic mechanism in breast cancer.

Insulin receptor and IGF1R are not required for oocyte growth, differentiation, and maturation in mice.

In mammals, insulin and insulin-like growth factors (IGFs: IGF1 and IGF2) act through 2 structurally related receptors, the insulin receptor (INSR) and the type 1 IGF receptor (IGF1R), both of which are expressed in developing oocytes. IGF1 plays an important role in female reproduction, and female Igf1 knockout mice fail to ovulate and are infertile. On the other hand, little is known about the in vivo role of the insulin signaling pathway in oocytes during follicular development, although exposure to insulin or IGF1 in vitro improves oocyte maturation. To further address the significance of insulin/IGF signaling, we used conditional mutant mice and ablated the function of the genes encoding INSR, IGF1R, or both receptors specifically in developing mouse oocytes. Our genetic evidence showed unexpectedly that the female reproductive functions are not affected when Insr, Igf1r or both Insr;Igf1r are ablated in oocytes, as the female mice are fertile and exhibit normal estrous cyclicity, oocyte development and maturation, parturition frequency, and litter size. In view of these novel observations indicating that the insulin/IGF signaling is not essential in oocytes, the IGF1-dependent female fertility is re-evaluated and discussed.