Differential effects of aromatase inhibitors and antiestrogens on estrogen receptor expression in breast cancer cells.
BACKGROUND
Estrogen receptors (ER) alpha and beta play an important role in breast cancer. Recently, systemic adjuvant endocrine therapy with selective estrogen receptor modulator (SERM) tamoxifen has been challenged by aromatase inhibitors. Compared to antiestrogens, third-generation aromatase inhibitors (anastrozole and letrozole) exhibit an improved efficacy and tolerability.


METHODS
Using real-time PCR analysis, 21 breast cancer tissue samples were analysed for a change of the ERalpha/ERbeta ratio during malignant progression. In stimulation experiments, differential effects of SERMs, ER antagonists and aromatase inhibitors have been investigated.


RESULTS
Transition from normal breast to grade 1 tumors was characterized by down-regulation of ERbeta (relative quantification [RQ]=0.83, p=0.019), while transition from grade 1 to grade 3 tumors was associated with the decrease of ERalpha expression (RQ=1.14 vs. RQ=0.65, p<0.001). In stimulation assays, tamoxifen and fulvestrant increased ERalpha expression to RQ=1.51 (p=0.01) and RQ=1.42 (p<0.001), respectively, and left ERbeta unchanged. In contrast, aromatase inhibitors up-regulated ERbeta to RQ=1.23 (anastrozole, p=0.029) and RQ=1.38 (letrozole, p=0.048).


CONCLUSIONS
Taken together, data indicate that SERMs/antiestrogens and aromatase inhibitors exhibit opposed effects on the ER expression of breast cancer cells: tamoxifen and fulvestrant up-regulate ERalpha expression, while aromatase inhibitors increase ERbeta expression, which may contribute to the aromatase inhibitors' therapeutic superiority over antiestrogens.
Smollich
Martin
M
Department of Obstetrics and Gynecology, University of Münster, 48129 Münster, Germany.
Götte
Martin
M
Fischgräbe
Jeanett
J
Radke
Isabel
I
Kiesel
Ludwig
L
Wülfing
Pia
P
D000077384:Anastrozole; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000627:therapeutic use; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D000077289:Letrozole; D009367:Neoplasm Staging; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism; D009570:Nitriles / Q000627:therapeutic use; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000627:therapeutic use; D014230:Triazoles / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D047072:Aromatase Inhibitors; C506487:ESR1 protein, human; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D009570:Nitriles; D012333:RNA, Messenger; D014230:Triazoles; D013629:Tamoxifen; D000077267:Fulvestrant; D000077384:Anastrozole; D004958:Estradiol; D000077289:Letrozole