Our studies suggest that the window of opportunity for effective breast cancer prevention using EGFR inhibitors is a state at which loss of BRCA1 and gain of EGFR have occurred, but the growth factor independence selleck chemicals of cancer cells has not yet been established. Conclusions We have identified a cooperative effect of loss of BRCA1 with gain of EGFR expression that leads to increased clonal proliferation of MECs and may render these cells vulnerable to malignant transformation. This coopera tive effect is achieved by transcriptional upregulation as well as posttranslational stabilization of EGFR upon BRCA1 downregulation. In addition, cells with loss of BRCA1 are enriched for the highly EGFR expressing ALDH1 positive population.

The tumorigenic effect of the cooperation of loss of BRCA1 with gain of EGFR in nonmalignant MECs can be disrupted by the preventive use of the EGFR inhibitor erlotinib. Thus, at the prema lignant stage, EGFR inhibition may provide Inhibitors,Modulators,Libraries a window of opportunity for breast cancer prevention. Estrogen plays a key role in the pathogenesis of breast cancer. The cellular response to estrogen is mediated by two estrogen receptor isoforms, ERa and ERb. ER is the primary target for chemoprevention and endocrine therapy in breast cancer and provides prog nostic and predictive information about tumour response to endocrine treatment. A series of reports strongly indicated that estrogens, via ERa, stimulate proliferation and inhibit apoptosis, whereas ERb opposes the proliferative effect of ERa in vitro. The alteration of the intracellular ERa ERb ratio affects the estrogen induced cellular response.

In addition Inhibitors,Modulators,Libraries to its role in modulating ERa mediated regulation, ERb also has distinct functions. Expression of ERb signifi cantly reduced cancer cell Inhibitors,Modulators,Libraries proliferation and tumour growth in severe combined immunodeficient mice. ERb inhibited proliferation of colon cancer cells. It was suggested that the loss of ERb expression may be one of the events leading to cancer development. Hypoxia regulates a set of cellular functions, such as increased angiogenesis, energy metabolism, and erythro poiesis. The adaptive response to hypoxia is con trolled primarily by hypoxia inducible factors, which are master regulators of hypoxic gene expression and oxygen homeostasis.

Inhibitors,Modulators,Libraries HIF 1 plays a role in the physiologic regulation of a number of genes, such as vas cular endothelial growth factor, erythropoietin, and glucose transporter 1 expression in various tissues. HIF 1 functions as a heterodimer, comprised of an oxygen labile a subunit Inhibitors,Modulators,Libraries and a stable b subunit, also referred to as aryl hydrocarbon receptor nuclear transloca tor. The HIF 1a subunit LB42708? is degraded through a proteasome pathway under normoxia, whereas ARNT is constitutively expressed and located in the nucleus.