Abstract
Aromatase inhibitors (AIs) have a central role in the treatment of breast cancer; however, resistance is a major obstacle to optimal management. Evidence from endocrine, molecular and pathological measurements in clinical material taken before and after therapy with AIs and data from clinical trials in which AIs have been given as treatment either alone or in combination with other targeted agents suggest diverse causes for resistance. These include inherent tumour insensitivity to oestrogen, ineffective inhibition of aromatase, sources of oestrogenic hormones independent of aromatase, activation of signalling by non-endocrine pathways, enhanced cell survival and selection of hormone-insensitive cellular clones during treatment.
Highlights
Some breast cancers require oestrogens for growth and, if deprived of these hormones, will regress
Adaptive changes with aromatase inhibitor (AI) treatment, such as increased/ changed expression of HER2 and oestrogen receptor (ER) co-regulators and loss of ER, have been described
In order to understand the nature of resistance to AIs, this review has drawn upon endocrine, molecular and pathological measurements made in clinical material taken before and after therapy with AIs and upon observations from clinical trials in which AIs have been given as treatment either alone or in combination with other targeted agents
Summary
Some breast cancers require oestrogens for growth and, if deprived of these hormones, will regress. Cell survival Most tumours that appear clinically resistant to AI are molecularly sensitive to the drugs insofar as the expression of both oestrogen-regulated and proliferation-associated genes and proteins decreases with treatment [13,14,58] To explain this form of resistance, it is necessary to suggest that the therapeutic reduction in proliferation leaves residual cell cycling which, together with efficient cell survival mechanisms, maintains tumour growth. Adaptive changes with AI treatment, such as increased/ changed expression of HER2 and ER co-regulators and loss of ER, have been described ( most breast cancers with acquired resistance to AIs remain ERpositive after treatment [12,71])
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