Estrogen receptor beta/alpha ratio predicts response of pancreatic cancer cells to estrogens and phytoestrogens.
BACKGROUND
Reports on hormone receptor expression of pancreatic cancer (PaCa) cells and treatment responses to antihormonal therapy are conflicting. We examined estrogen receptor (ER) expression in PaCa cells and investigated its function in estrogen-mediated cell proliferation.


METHODS
Protein levels of ERalpha and ERbeta in 8 human PaCa lines were detected by Western blot analysis. Cell proliferation was measured by sulforhodamine B analysis. ER modulators included diethylstilbestrol (DES), estradiol (E2), 4-hydroxytamoxifen (Tam), genistein (Gen), and Coumestrol (Coum).


RESULTS
ERalpha levels were detected in all eight, and ERbeta in seven cell lines. ERbeta/ERalpha ratio ranged from 0.4 to 111 (median: 6.4, >5 in seven lines). Median maximal growth stimulation (in %, observed at 20 to 200 nM) was 19 (DES), 39 (E2), 20 (Tam), 22 (Gen), and -9 (Coum); median maximal inhibition (at 40 to 60 microM) was 59 (DES), 36 (E2), 25 (Tam), 43 (Gen), and 50 (Coum). The extent of E2 and Gen stimulatory effects correlated with the ERbeta/ERalpha ratio (Kendall's tau: 0.714, P = 0.024), but not ERalpha or ERbeta levels alone. Only Coum-induced inhibition correlated with the ERbeta/ERalpha ratio (P = 0.006) and with ERalpha expression (r = 0.753, P = 0.03). Gemcitabine-induced PaCa cytotoxicity (at IC(40)) was significantly reduced by E2, Gen, and Coum.


CONCLUSIONS
PaCa proliferation in vitro is highly estrogen sensitive, and in contrast to other reports, ERs are frequently expressed. In 7/8 cell lines, ERbeta expression outweighs ERalpha expression. The impact of the ERbeta/ERalpha ratio on estrogen-mediated growth stimulation and reduced cytotoxicity at physiological concentrations may have clinical implications on PaCa therapy.
Konduri
Srivani
S
Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Division of Surgical Oncology, The Cancer Institute of New Jersey, New Brunswick, New Jersey 08901, USA.
Schwarz
Roderich E
RE
D000964:Antimetabolites, Antineoplastic / Q000633:toxicity; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003375:Coumestrol / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000633:toxicity; D004054:Diethylstilbestrol / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011237:Predictive Value of Tests; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004968:Estrogens, Non-Steroidal; D013629:Tamoxifen; D003841:Deoxycytidine; C016601:afimoxifene; D004958:Estradiol; D004054:Diethylstilbestrol; D019833:Genistein; D003375:Coumestrol; D000093542:Gemcitabine