The
estrogen receptor alpha (
ERalpha) has proven to be the single most important target in
breast cancer over the last 30 years. The use of the selective ER modulator (
SERM)
tamoxifen for the treatment and prevention of
breast cancer has changed
therapeutics. The
SERM raloxifene, approved for the treatment of
osteoporosis, lacks
tamoxifen's increased risk for
endometrial cancer and is being evaluated for the prevention of
breast cancer. Other
SERMs approved or under development for use against
breast cancer or
osteoporosis include
toremifene,
GW5638, GW7604 (the active metabolite of
GW5638),
idoxifene,
lasofoxifene,
arzoxifene,
bazedoxifene,
EM-800 and
acolbifene (the active metabolite of
EM-800).
Aromatase inhibitors (AIs) have recently proven to be more efficacious than
tamoxifen as first-line
therapy, efficacious for second-line
therapy (e.g. against
tamoxifen-resistant disease), and useful for extended adjuvant
therapy after
tamoxifen. The AIs include the non-steroidal agents
letrozole and anastrole, and the steroidal agent
exemestane. The pure
antiestrogen fulvestrant has proven to be just as effective as AIs. Other pure
antiestrogens,
ZK-703,
ZK-253,
RU 58668 and TAS-108 show great promise. The development of resistance to endocrine
therapy remains a clinically important problem, and laboratory models based on human
breast cancer cells grown as
tumors in immune-compromised mice have led to important insights into this problem.
Progesterone receptor-negative status of ER-positive breast
cancers may reflect altered
growth factor receptor signaling, and helps to explain why this subclass of
tumors exhibits lower response rates to
tamoxifen compared to
cancers typed
progesterone receptor-positive. Crosstalk among plasma membrane-localized ER,
growth factor receptor signaling, and nuclear-localized ER provide further insights into antihormonal-resistant
breast cancer.