Since we detected both pro survival BP1 and selleck chem inhibitor pro death pathways in LCC9 cell in glutamine only condition, we e amined cell survival in these cells beyond 72 h. We followed cell growth in LCC9 cells beyond 72 h for all four conditions glutamine glucose, no glucose no glutamine, glucose no glutamine, and no glucose glutamine. While 100% of the cells sur vived in glutamine glucose conditions, no cells survived in no glucose no glutamine or glucose no glutamine conditions. Most LCC9 cells underwent apoptosis in no glucose glutamine conditions within 72 h, however, a small number of cells survived. We followed the growth of these cells for 12 weeks. Cell num ber in LCC9Gln cells was significantly slower than in LCC9 cells grown in complete media.

Moreover, LCC9Gln cells showed an increased in GLS GAC e pression but a decrease in GLUL, MYC, and MA e pression. Table 1 summarizes the levels of MYC protein and cell fate at 72 h and 72 h in LCC9 cells in the presence of glutamine and or glucose. In summary, when glutamine and glucose are abundant, MYC promotes their uptake and uniquely controls GLS and GLUL e pression in anti estrogen resistant breast cancer cells. In glucose deprived conditions when glutamine is present, the UPR is triggered and apoptosis is induced through GRP78 IRE1 JNK CHOP within 72 h. However, a small number of cells use the UPR to maintain survival beyond 72 h through GRP78 IRE1 BP1, albeit at a lower growth rate, by adjusting MYC to promote glutamine metabolism. Discussion MYC is a target of estrogen signaling in breast cancer cells that can control diverse aspects of cancer cell survival including cellular metabolic reprogramming.

Activation of MYC has been linked to acquired antiestrogen resistance in human breast tumors and poor clinical outcome. Our findings show that MYC driven pro survival signaling in antiestrogen resist ant breast cancer is partially dependent on proteins that control the cell cycle and apoptosis. While rapid drug metabolism limits the efficacy of 10058 F4 as an antitu mor agent for solid tumors, its use in vitro showed that inhibiting MYC in antiestrogen resistant breast can cer cells confirmed the essential role of MYC activation in driving this phenotype. Metabolically stable small molecule inhibitors of MYC hold significant Cilengitide promise as new agents to treat some drug resistant breast tumors. MYC is an important regulator of glutamine and glucose metabolism. Antiestrogen resistant breast cancer cells with higher MYC activation showed increased sensitivity to small molecule inhibitors of glutaminolysis and glycoly sis, but did not re sensitize these cells to antiestrogens. Thus, activation of these metabolic path ways in resistant cells may be independent of ER mediated signaling.