In vitro and in vivo Effects of Combination of Trastuzumab (Herceptin) and Tamoxifen in Breast Cancer

Abstract

Extensive interactions between estrogen receptor alpha (ERalpha) and HER2 signaling pathways have been described. Using BT-474 human breast cancer cells, we have previously shown that the combination of tamoxifen (TAM) and Herceptin results in strong synergistic growth inhibition, enhancement of G(0)-G(1) cell cycle accumulation, inhibition of HER2 activity and a cytostatic effect without cell death. To further examine the underlying mechanism of synergy, we investigated the effect of this drug combination on ERalpha function and growth factor downstream signaling. TAM caused a small increase in ERalpha levels while Herceptin had no effect, and both drugs caused an increase in the level of Ser118-phosphorylated ERalpha. However, both TAM and Herceptin individually inhibited ERalpha transcriptional activity, although the combination did not have a greater effect than either single agent. Herceptin inhibited MAPK and Akt activity, while TAM had no effect on these either as a single agent or when added to Herceptin. Using a BALB/c athymic BT-474 in vivo xenograft model, the drug combination (Herceptin 0.3 mg/kg i.p. twice weekly, TAM 1.0 mg/mouse i.p. three times per week) showed a greater inhibition of tumor growth compared to either single agent. Tumor extracts and fixed sections were examined at the end of the treatment period for treatment-specific alterations: we noted a paradoxical proliferation-inducing effect of TAM that was reversed by the addition of Herceptin. Our results indicate that combined targeting of both peptide growth factor receptors and ERalpha represents a promising breast cancer treatment strategy.

Off-target-free gene delivery by affinity-purified receptor-targeted viral vectors

“…2c; Supplementary Fig. 6, Supplementary Table 1), as expected from its well-described cytostatic action 14 . Consequently, Her2-AAVtreated mice survived significantly longer than Herceptin-treated mice (Fig.…”

Trastuzumab inhibits the growth of human gastric cancer cell lines with HER2 amplification synergistically with cisplatin

“…In SK-BR-3 and BT-474, trastuzumab was shown to inhibit the phosphorylation of AKT and ERK, which was in accordance with the growth inhibitory effect (8,16). We postulated that trastuzumab works in the same manner in gastric cancer cell lines with HER2 amplification, so phosphorylation of HER2 and downstream molecules related to the pathways would be inhibited by trastuzumab.…”

Controlled internalization of Her-2/neu receptors by cross-linking for targeted delivery

“…Female athymic mice were inoculated in a right thoracic mammary fat pad with 1 x 10 7 BT-474 cells mixed with equal volume Matrigel, 24 h following the subcutaneous implantation of a sixty day release 0.72 mg b-estradiol pellet. 17 For MCF-7 breast tumor mouse xenografts, 2 x 10 6 MCF-7 cells were inoculated in a mammary fat pad of a female SCID mouse previously inoculated with a sixty day release 0.18 mg b-estradiol pellet. Tumors were grown to an average volume of 0.5 cm 3 .…”