NASHVILLE, Tenn--Inhibition of transforming growth factor-beta (TGF-beta)
may enhance the activity of tamoxifen (Nolvadex) in breast cancer and restore
tamoxifen sensitivity to resistant cells, according to results of laboratory
experiments at the Vanderbilt Cancer Center and Georgetown's Lombardi Cancer
Carlos Arteaga, MD, associate professor of medicine and cell biology
at Vanderbilt, said that neutralization of TGF-beta-2 by anti-TGF-beta
antibodies "totally inhibited progressive growth" of tamoxifen-resistant
human breast tumors implanted into mice that were subsequently treated
with tamoxifen. The finding suggests that "neutralization of TGF-beta
in this intact host had restored tamoxifen sensitivity," he added.
Dr. Arteaga and his colleagues have conducted a series of laboratory
experiments to explore the relationship between TGF-beta-2 and breast tumor
response to tamoxifen.
First, they studied the effects of tam-oxifen on the LCC-1 and LCC-2
breast cancer cell lines, the latter of which are tamoxifen resistant and
also overexpress TGF-beta-2. The studies showed that LCC-2 cells are highly
resistant to both natural killer (NK) and lymphokine-activated killer (LAK)
cells, consistent with the overexpression and immunosuppressive potential
Subsequent studies evaluated the ability of tamoxifen to modulate tumor
cells' sensitivity to NK and LAK. In LCC-1 cells, tamoxifen significantly
increased the cytotoxic activity of NK and LAK, but LCC-2 cells remained
resistant, Dr. Arteaga said in his report of the findings at a general
session of the San Antonio Breast Cancer Symposium.
Another series of studies evaluated the effect of tamoxifen on NK activity
in mice that were tumor free or implanted with LCC-1 or LCC-2 tumors. Tamoxifen
induced NK function in the tumor-free and LCC 1-bearing animals but not
in animals with LCC-2, again suggesting the overexpression of TGF-beta-2.
"With this data, we proposed a model by which tamoxifen would enhance
NK activity," Dr. Arteaga said. "At least in breast cancer sensitive
systems, this might, in part, mediate tamoxifen's antitumor activity. In
cells that overexpress TGF-beta-2, the overexpression may counteract NK
function, hence explaining tamoxifen resistance."
To evaluate the model, the investigators introduced LCC-2 tumors into
mice. The tumors were allowed to grow to a size of 100 mm3. The animals
then received 25 mg of tamoxifen and were randomized to anti-TGF antibody
or an IgG-2 control. Animals given the antibody had total inhibition of
"When we looked at NK function in LCC-2 tumors in the setting of
tamoxifen, we found that those animals treated with the antibody now had
up-regulation of NK, which was not present in the animals treated with
the control IgG-2," Dr. Arteaga said. "The finding suggested
that the up-regulation of NK function was important for restoration of
The experiments were repeated in animals that lack NK activity. Tumor
growth curves overlapped in animals treated with the anti-TGF antibody
or IgG-2. The finding provided support for the concept that up-regulation
of NK activity is mediated by TGF-beta-2 and is essential to tamoxifen's
Taken together, the data lead to the following conclusions, Dr. Arteaga
- Tamoxifen-stimulated host immune functions may, in part, mediate the
antitumor effects of antiestrogens.
- Tumor cell overexpression of immunosuppressive cytokines, such as TGF-beta-2,
may lead to tamoxifen inhibition.
- Inhibition of TGF-beta-2 overex-pression in breast tumor cells may
enhance tamoxifen-mediated antitumor effects.