Novel antitumor effect of estradiol in athymic mice injected with a T47D breast cancer cell line overexpressing protein kinase Calpha.
OBJECTIVE
Resistance to tamoxifen (TAM) represents a significant challenge to the management of breast cancer. We previously reported that the estrogen receptor (ER)-negative hormone-independent T47D:C42 cell line has both elevated protein kinase Calpha (PKCalpha) protein expression and basal activator protein-1 activity compared with the parental ER+ (hormone-dependent) T47D:A18 cell line. Stable transfection of PKCalpha to the T47D:A18 breast cancer cell line results in increased basal activator protein-1 activity, reduced ER function, increased proliferation rate, and hormone-independent growth (Tonetti et al., Br. J. Cancer, 83: 782-791, 2000). In this report, we further characterize the role of PKCalpha overexpression in vivo to elucidate a possible molecular mechanism of tamoxifen resistance.


METHODS
To determine whether the T47D:A18/PKCalpha cell line would produce hormone-independent tumors in athymic mice, we injected T47D:A18, T47D:A18/neo, or the T47D:A18/PKCalpha20 cell clones bilaterally into the mammary fat pads of athymic mice. Tumor growth was evaluated following treatment with estradiol (E2), TAM, and the pure antiestrogen, ICI 182,780.


RESULTS
Mice receiving either T47D:A18 or T47D:A18/neo cells produced tumors that grew in response to E2 treatment, whereas the untreated control and TAM-treated groups showed no tumor growth. Interestingly, mice receiving the T47D:A18/PKCalpha20 clone produced tumors in both the control and TAM groups, whereas tumor growth was inhibited in mice treated with E2. PKCalpha was also overexpressed in an MCF-7 tumor model that also exhibited TAM-stimulated and E2-induced regression.


CONCLUSIONS
These results suggest that overexpression of PKCalpha in breast tumors results in hormone-independent tumor growth that cannot be inhibited by TAM treatment. Furthermore, the finding that E2 has an antitumor effect on breast tumors overexpressing PKCalpha is a novel observation that may have important therapeutic implications.
Chisamore
M J
MJ
Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, IL 60611, USA.
Ahmed
Y
Y
Bentrem
D J
DJ
Jordan
V C
VC
Tonetti
D A
DA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D004965:Estrogen Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D047628:Estrogen Receptor alpha; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007527:Isoenzymes / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D011493:Protein Kinase C / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D011960:Receptors, Estrogen / Q000378:metabolism; D013997:Time Factors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D007527:Isoenzymes; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D004958:Estradiol; C496628:PRKCA protein, human; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha