Five-year breast can?cer sur?vival rates have improved dra?mat?i?cally over the past 50 years, but tumors can recur up to 10 or more years after they are detected. When tumors recur, they are even more dif?fi?cult to treat. Recur?ring breast tumors often don?t respond to tar?geted drugs, even if the ini?tial tumor did, and they metastasize?spread to other parts of the body?more eas?ily. To help women bat?tling breast can?cer, Eric Pross?nitz, is inves?ti?gat?ing GPER, a new type of estro?gen recep?tor, as a pos?si?ble new drug target.
Unlike ?clas?si?cal? estro?gen recep?tors, GPER resides on cell mem?branes rather than in the cell?s nucleus. Pross?nitz is a Uni?ver?sity of New Mex?ico Pro?fes?sor of Cell Biol?ogy & Phys?i?ol?ogy and Co-Leader of the Women?s Can?cers Pro?gram at the UNM Can?cer Cen?ter. He recently received a five-year, $1.6 mil?lion grant from the National Can?cer Insti?tute to study GPER, its role in resis?tance to drugs that tar?get estro?gen recep?tors, and pos?si?ble new ways to tar?get it in com?bat?ing breast cancer.
Like other cell mem?brane recep?tors, GPER tells the cell what?s hap?pen?ing around it. Much like humans see and hear their sur?round?ings, each cell has dif?fer?ent types of recep?tors to sense its envi?ron?ment. For exam?ple, breast cells have mul?ti?ple recep?tors, includ?ing hor?mone recep?tors that sense estro?gen and prog?es?terone and a group of recep?tors that senses growth fac?tors, which includes the HER2 receptor.
Most breast can?cer drugs tar?get one or more of these recep?tors. Women whose breast can?cer cells lack all three recep?tors, called triple neg?a?tive breast can?cers, must resort to surgery, chemother?apy and radi?a?tion. Pross?nitz dis?cov?ered in pre?vi?ous research that Tamox?ifen, a breast can?cer drug that works by inhibit?ing ER recep?tors, acti?vates GPER. Now Pross?nitz wants to deter?mine whether and how GPER influ?ences breast tumor growth and metastasis.
Pross?nitz is col?lab?o?rat?ing with Helen Hath?away, UNM Pro?fes?sor of Cell Biol?ogy & Phys?i?ol?ogy and a mem?ber of the Women?s Can?cers Pro?gram, to con?duct stud?ies on GPER. In the first study, Pross?nitz and Hath?away will use can?cer?ous and non-cancerous breast cells to dis?cover the dif?fer?ences in bio?chem?i?cal reac?tions that estro?gen recep?tors and GPER trig?ger. Both recep?tors ulti?mately stim?u?late enzymes that reg?u?late cell growth and sur?vival, but researchers know lit?tle about how the cas?cades of cel?lu?lar reac?tions dif?fer. Under?stand?ing this bio?chem?istry will help Pross?nitz and Hath?away explain how breast can?cer cells respond to estro?gen and become resis?tant to Tamox?ifen, poten?tially result?ing in bet?ter long-term breast can?cer therapies.
In the sec?ond set of stud?ies, Pross?nitz and Hath?away will use mice lack?ing the gene for GPER to deter?mine whether GPER affects how breast can?cers form and progress. They will also eval?u?ate whether GPER affects the abil?ity of the pri?mary tumors to metastasize.
Pross?nitz explains, ?The pri?mary tumor rarely kills women. But when the tumor spreads to another site in the body and affects the func?tion of an organ, that can kill.? Pross?nitz and Hath?away will also test dif?fer?ent com?bi?na?tions of drugs to develop poten?tial ther?a?pies that could inhibit both ER, the dom?i?nant estro?gen recep?tor in breast can?cers, and GPER recep?tors. Such a ther?apy could pre?vent acquired resis?tance to exist?ing breast can?cer drugs and tar?get?ing GPER alone could be a new strat?egy for triple neg?a?tive breast cancers.
In their final set of stud?ies, Pross?nitz and Hath?away will use small pieces of live human breast tumors and nor?mal breast tis?sue to test dif?fer?ent ther?a?pies and GPER func?tion. These small pieces of tis?sue include not only the breast cells, can?cer?ous or not, but also the sur?round?ing cells and matrix. ?Cells behave very dif?fer?ently in tis?sues,? explained Pross?nitz. ?They respond to what their neigh?bors are doing, and to the kinds of neigh?bor?ing cells. To under?stand their behav?ior in peo?ple, we have to study the cells in the envi?ron?ment sim?i?lar to what they had in the person.?
This set of stud?ies will also test if the ther?a?pies that work for mouse breast tumors can also work in human breast can?cers. ?We need to under?stand how the whole tis?sue actu?ally responds. It?s a cru?cial step towards clin?i?cal tri?als,? he?added.
Before ini?ti?at?ing clin?i?cal tri?als, researchers must demon?strate that the drugs are safe for humans in pre?clin?i?cal tri?als. But Pross?nitz and Hath?away are encour?aged. ?Our com?pounds are not toxic to mice, even at very high doses,? says Hath?away. Even so, clin?i?cal tri?als are years away because can?cer is such a com?plex dis?ease. ?Nev?er?the?less, this is an excit?ing new tar?get for the treat?ment of mil?lions of women with breast can?cer,? says Prossnitz.
And for them, a new tar?get means new?hope.
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