November 11, 2003
Estrogen Shrinks Some Breast Tumors
CHICAGO ---
Striking, paradoxical discoveries by Northwestern University
researchers suggest that low levels of estrogen – the
same hormone that promotes breast cancer in its early stages – can
shrink breast tumors that have developed resistance to the drugs
tamoxifen and raloxifene.
The findings are described in two studies by V. Craig Jordan
and co-researchers at The Robert H. Lurie Comprehensive Cancer
Center of Northwestern University that were published in the Nov.
5 issue of the Journal of the National Cancer Institute.
Jordan is Diana, Princess of Wales, Professor of Cancer Research,
professor of molecular pharmacology and biological chemistry at
the Feinberg School of Medicine and director, Lynn Sage Breast
Cancer Research Program at the Cancer Center.
Tamoxifen is a selective estrogen receptor modulator (SERM) used
to treat estrogen receptor-positive breast cancers and prevent
recurrence of the disease. However, tamoxifen loses effectiveness
after five years and can subsequently stimulate breast cancer growth.
New endocrine therapies, such as aromatase inhibitors and the antiestrogen
fulvestrant, are used to boost the effects of tamoxifen, although
some studies suggest that low levels of estrogen may also inhibit
the growth of tamoxifen-stimulated breast tumors.
Clodia Osipo, who is lead author on the tamoxifen article, Jordan
and Cancer Center colleagues examined the effect of tamoxifen,
the estrogen estradiol and fulvestrant, both alone and in various
combinations, in a laboratory model of tamoxifen-stimulated human
breast cancer.
The researchers found that low levels of estradiol caused tamoxifen-resistant
breast tumors to regress, apparently by increasing cell suicide,
or apoptosis, through decreased expression of the antiapoptotic
factors Her2/neu and NF-_B and increased expression of the death
receptor protein Fas, with regulates apoptosis.
Combined treatment with fulvestrant plus estadiol unexpectedly
promoted the growth of tamoxifen-stimulated breast tumors, suggesting
that use of fulvestrant in patients with sufficient levels of circulating
estrogen may actually stimulate tumor growth.
In the second study, Hon Liu, Jordan and Cancer Center co-researchers
examined whether low doses of estradiol would also have an effect
on raloxifene-resistant breast cancer cells. Widespread use of
the SERM raloxifene for the prevention of osteoporosis has raised
concerns that such women may develop breast cancers that are resistant
to raloxifene.
Treatment of cultured raloxifene-resistant breast cancer cells
with estradiol for 12 to 24 days inhibited cell growth compared
with untreated control cells. Estradiol treatment also caused a
decrease in NF-_B activity, an increase in the expression of the
Fas protein and an increase in apoptosis.
The researchers also found that raloxifene-resistant cells were
also resistant to tamoxifen, suggesting that tamoxifen would not
be effective against breast cancers that are resistant to raloxifene.
In addition, mice with drug-resistant tumors experienced tumor
shrinkage after five weeks of estradiol treatment.
Together,
these studies “suggest that it is possible for
a patient’s own estrogen to act as an anticancer agent in
SERM-resistant breast cancers,” Jordan said.
“Clearly, a clinical strategy to use an aromatase inhibitor
after SERM resistance may have some short-term benefit for patients,
but it is possible that a novel strategy of briefly treating women
with estrogen before re-instituting estrogen-deprivation therapy
may benefit certain women,” Jordan said. |