Mechanisms of resistance to aromatase inhibitors.
Aromatase inhibitors are rapidly becoming the first choice for hormonal treatment of steroid receptor positive breast cancer in postmenopausal women. An understanding of the resistance mechanisms to these agents is, therefore, important for the appropriate delivery of treatment to responsive patients and the rational development of new agents targeted at the resistance pathways. De novo resistance appears to be a quantitative rather than qualitative phenomenon with virtually all oestrogen receptor positive tumours showing an anti-proliferative response to the aromatase inhibitor anastrozole. While the expression of type 1 growth factor receptors reduces response to tamoxifen this appears to have little detrimental effect on response to aromatase inhibitors. Studies of acquired resistance in vitro have indicated that acquisition of hypersensitivity to oestrogenic stimulation is a key mechanism that is dependent on enhanced cross-talk of growth factor and oestrogen signaling pathways. Collection of resistant biopsy tissues from patients is important to determine if this mechanism is clinically relevant.
Academic Department of Biochemistry, Royal Marsden Hospital, London SW3 6JJ, UK. mitch.dowsett@icr.ac.uk
Mitch
M
Dowsett
Lesley-Ann
LA
Martin
Ian
I
Smith
Stephen
S
Johnston
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006801:Humans; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction
D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D004967:Estrogens; D011960:Receptors, Estrogen