Targeting the AIB1 oncogene through mammalian target of rapamycin inhibition in the mammary gland.
Amplified in breast cancer 1 (AIB1), an estrogen receptor (ER) coactivator, is frequently amplified or overexpressed in human breast cancer. We previously developed a transgenic mouse model in which AIB1 can act as an oncogene, giving rise to a premalignant hyperplastic mammary phenotype as well as to a high incidence of mammary tumors that are primarily ER(+). In this model, the AIB1 transgene is responsible for continued activation of the insulin-like growth factor-I receptor, suggesting a role for the activation of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway in the premalignant phenotype and tumor development. Here we show that treatment of AIB1 transgenic mice with the mTOR inhibitor RAD001 reverts the premalignant phenotype. Furthermore, treatment of cell lines derived from AIB1-dependent mammary tumors with RAD001 in culture leads to a G(1) cell cycle arrest. Lastly, tumor growth after injection of ER(+) AIB1 tumor cell lines into wild-type animals is inhibited by RAD001 treatment. In this ER(+) model, inhibition of tumor growth by RAD001 was significantly better than inhibition by the antiestrogen 4-hydroxytamoxifen alone, whereas a combination of both RAD001 and 4-hydroxytamoxifen was most effective. Based on these results, we propose that the combination of mTOR inhibition and ER-targeted endocrine therapy may improve the outcome of the subset of ER(+) breast cancers overexpressing AIB1. These studies provide preclinical support for the clinical development of RAD001 and suggest that AIB1 may be a predictive factor of RAD001 response.
Torres-Arzayus
Maria I
MI
Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Yuan
Jing
J
DellaGatta
Jamie L
JL
Lane
Heidi
H
Kung
Andrew L
AL
Brown
Myles
M
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004714:Endometrial Hyperplasia / Q000139:chemically induced / Q000517:prevention & control; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D000068338:Everolimus; D005260:Female; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000502:physiology; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D056921:Nuclear Receptor Coactivator 3; D009857:Oncogenes / Q000235:genetics / Q000502:physiology; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D011494:Protein Kinases / Q000502:physiology*; D011960:Receptors, Estrogen / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D013629:Tamoxifen / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology; D014407:Tumor Cells, Cultured
D047628:Estrogen Receptor alpha; D007166:Immunosuppressive Agents; D011960:Receptors, Estrogen; D015534:Trans-Activators; D013629:Tamoxifen; C016601:afimoxifene; D000068338:Everolimus; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus