Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide.
BACKGROUND
The androgen receptor (AR) is widely expressed in breast cancers and has been proposed as a therapeutic target in estrogen receptor alpha (ER) negative breast cancers that retain AR. However, controversy exists regarding the role of AR, particularly in ER + tumors. Enzalutamide, an AR inhibitor that impairs nuclear localization of AR, was used to elucidate the role of AR in preclinical models of ER positive and negative breast cancer.


METHODS
We examined nuclear AR to ER protein ratios in primary breast cancers in relation to response to endocrine therapy. The effects of AR inhibition with enzalutamide were examined in vitro and in preclinical models of ER positive and negative breast cancer that express AR.


RESULTS
In a cohort of 192 women with ER + breast cancers, a high ratio of AR:ER (≥2.0) indicated an over four fold increased risk for failure while on tamoxifen (HR = 4.43). The AR:ER ratio had an independent effect on risk for failure above ER % staining alone. AR:ER ratio is also an independent predictor of disease-free survival (HR = 4.04, 95% CI: 1.68, 9.69; p = 0.002) and disease specific survival (HR = 2.75, 95% CI: 1.11, 6.86; p = 0.03). Both enzalutamide and bicalutamide inhibited 5-alpha-dihydrotestosterone (DHT)-mediated proliferation of breast cancer lines in vitro; however, enzalutamide uniquely inhibited estradiol (E2)-mediated proliferation of ER+/AR + breast cancer cells. In MCF7 xenografts (ER+/AR+) enzalutamide inhibited E2-driven tumor growth as effectively as tamoxifen by decreasing proliferation. Enzalutamide also inhibited DHT- driven tumor growth in both ER positive (MCF7) and negative (MDA-MB-453) xenografts, but did so by increasing apoptosis.


CONCLUSIONS
AR to ER ratio may influence breast cancer response to traditional endocrine therapy. Enzalutamide elicits different effects on E2-mediated breast cancer cell proliferation than bicalutamide. This preclinical study supports the initiation of clinical studies evaluating enzalutamide for treatment of AR+ tumors regardless of ER status, since it blocks both androgen- and estrogen- mediated tumor growth.
Dawn R
DR
Cochrane
Sebastián
S
Bernales
Britta M
BM
Jacobsen
Diana M
DM
Cittelly
Erin N
EN
Howe
Nicholas C
NC
D'Amato
Nicole S
NS
Spoelstra
Susan M
SM
Edgerton
Annie
A
Jean
Javier
J
Guerrero
Francisco
F
Gómez
Satyanarayana
S
Medicherla
Iván E
IE
Alfaro
Emma
E
McCullagh
Paul
P
Jedlicka
Kathleen C
KC
Torkko
Ann D
AD
Thor
Anthony D
AD
Elias
Andrew A
AA
Protter
Jennifer K
JK
Richer
D000726:Androgen Antagonists / Q000627:therapeutic use*; D059002:Androgen Receptor Antagonists / Q000627:therapeutic use*; D000813:Anilides / Q000627:therapeutic use; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018572:Disease-Free Survival; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009570:Nitriles / Q000627:therapeutic use; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000627:therapeutic use; D014105:Tosyl Compounds / Q000627:therapeutic use; D014183:Transplantation, Heterologous
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D001549:Benzamides; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D013629:Tamoxifen; D010669:Phenylthiohydantoin; C540278:enzalutamide; C053541:bicalutamide