Novel antitumor effect of estradiol in athymic mice injected with a T47D breast cancer cell line overexpressing protein kinase C alpha

Purpose: Resistance to tamoxifen (TAM) represents a significant challenge t o the management of breast cancer. We previously reported that the estrogen receptor (ER)negative hormone-independent T47D:C42 cell line has both elev ated protein kinase C alpha (PKC alpha) protein expression and basal activa tor protein-1 activity compared with the parental ER+ (hormone-dependent) T 47D:A18 cell line. Stable transfection of PKC alpha to the T47D:A18 breast cancer cell line results in increased basal activator protein-1 activity, r educed ER function, increased proliferation rate, and hormone-independent g rowth (Tonetti et al., Br. J. Cancer, 83: 782-791, 2000). In this report, w e further characterize the role of PKC alpha overexpression in vivo to eluc idate a possible molecular mechanism of tamoxifen resistance. Experimental Design: To determine whether the T47D: A18/PKC alpha cell line would produce hormone-independent tumors in athymic mice, we injected T47D :A18, T47D:A18/neo, or the T47D:A18/PKC alpha 20 cell clones bilaterally in to the mammary fat pads of athymic mice. Tumor growth was evaluated followi ng treatment with estradiol (E2), TAM, and the pure antiestrogen, ICI 182,7 80. Results: Mice receiving either T47D:A18 or T47D:A18/neo cells produced tumo rs that grew in response to E2 treatment, whereas the untreated control and TAM-treated groups showed no tumor growth. Interestingly, mice receiving t he T47D:A18/PKC alpha 20 clone produced tumors in both the control and TAM groups, whereas tumor growth was inhibited in mice treated with E2. PKC alp ha was also overexpressed in an MCF-7 tumor model that also exhibited TAM-s timulated and E2-induced regression. Conclusions: These results suggest that overexpression of PKC alpha in brea st tumors results in hormone-independent tumor growth that cannot be inhibi ted by TAM treatment. Furthermore, the finding that E2 has an antitumor eff ect on breast tumors overexpressing PKC alpha is a novel observation that m ay have important therapeutic implications.