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An ideal strategy for ER positive infection could efficiently erase ER positive cells, thereby circumventing secondary resistance and obviating the requirement for long term endocrine treatment with its attendant quality Dub inhibitor of life detriment, chronic toxicity and cost. Targeting the professional success phosphatidylinositol 3 kinase signaling is exciting in this regard. Genes within the PI3K pathway are frequently mutated or amplified in ER positive breast cancer, suggesting that hyperactivation of PI3K signaling is an important target that, if effectively inhibited, can improve results. We have already shown that estrogen deprivation in combination with PI3K inhibition by RNA interference induces synthetic lethality and promotes cell death in ER positive breast cancer cell lines, offering a rational for combination techniques that target the ER and PI3K pathways simultaneously. ER optimistic breast cancers are genetically heterogeneous, however, and sensitivity may be modulated by cell intrinsic factors to this method. It's uncertain whether variations in PI3K process proteins particularly in PIK3CA, the gene that encodes the PI3Ka catalytic subunit sensitize tumors to this strategy. Furthermore, the optimal combinations of PI3K pathway inhibitors and hormonal Meristem agents haven't been recognized and the technique for people with estrogen deprivation resistant disease is unclear. Finally, a question has recently arisen concerning the relevance of the common PIK3CA mutation as a therapeutic target since several studies have suggested that PIK3CA mutation is of a favorable prognosis. If this is the situation, PIK3CA mutations could be likely to be unusual in high level disease and consequently less relevant as a therapeutic target in this setting. To address these dilemmas, a section of ER positive breast cancer cell lines with different PI3K pathway mutations were tested against three different PI3K pathway inhibitors, with selectivity Foretinib against either the rapamycin sensitive mammalian target of rapamycin complex, the PI3K catalytic isoforms or both PI3K and mTOR in the presence or absence of estrogen or ER downregulation by fulvestrant. Furthermore, these inhibitor combinations were re-tested after the growth of longterm estrogen deprivation resistance to type acquired resistance to estrogen deprivation. PIK3CA mutation analysis was performed on tumor biopsies from recurrent disease and in patients with stage 4 breast cancer to look for the prevalence of mutations in advanced disease and to correlate mutation position with the rate of tumor development and death. Pharmacological agents BKM120, BGT226 and RAD001 were obtained through material transfer agreements with Novartis. Fulvestrant, LY294002, rapamycin and 17b estradiol were from industrial sources. 17b Estradiol was dissolved in ethanol, inhibitors were dissolved in dimethyl-sulfoxide.