title: New hypotheses and opportunities in endocrine therapy: amplification of oestrogen-induced apoptosis.
abstract: OBJECTIVE
  To outline the progress being made in the understanding of acquired resistance to long term therapy with the selective oestrogen receptor modulators (SERMs, tamoxifen and raloxifene) and aromatase inhibitors. The question to be addressed is how we can amplify the new biology of oestrogen-induced apoptosis to create more complete responses in exhaustively antihormone treated metastatic breast cancer.
  
  
  RESULTS
  Three questions are posed and addressed. (1) Do we know how oestrogen works? (2) Can we improve adjuvant antihormonal therapy? (3) Can we enhance oestrogen-induced apoptosis? The new player in oestrogen action is GPR30 and there are new drugs specific for this target to trigger apoptosis. Similarly, anti-angiogenic drugs can be integrated into adjuvant antihormone therapy or to enhance oestrogen-induced apoptosis in Phase II antihormone resistant breast cancer. The goal is to reduce the development of acquired antihormone resistance or undermine the resistance of breast cancer cells to undergo apoptosis with oestrogen respectively. Finally, drugs to reduce the synthesis of glutathione, a subcellular molecule compound associated with drug resistance, can enhance oestradiol-induced apoptosis.
  
  
  CONCLUSIONS
  We propose an integrated approach for the rapid testing of agents to blunt survival pathways and amplify oestrogen-induced apoptosis and tumour regression in Phase II resistant metastatic breast cancer. This Pharma platform will provide rapid clinical results to predict efficacy in large scale clinical trials.
authors.affiliation: Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. v.craig.jordan@fccc.edu
authors.forename: V Craig
authors.initials: VC
authors.lastname: Jordan
authors.forename: Joan S
authors.initials: JS
authors.lastname: Lewis-Wambi
authors.forename: Roshani R
authors.initials: RR
authors.lastname: Patel
authors.forename: Helen
authors.initials: H
authors.lastname: Kim
authors.forename: Eric A
authors.initials: EA
authors.lastname: Ariazi
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D047072:Aromatase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D047072:Aromatase Inhibitors; D004967:Estrogens; C109584:GPER1 protein, human; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride; D004958:Estradiol