The prognostic biomarkers HOXB13, IL17BR, and CHDH are regulated by estrogen in breast cancer.
OBJECTIVE
We previously identified three genes, HOXB13, IL17BR, and CHDH, that strongly predict clinical outcome in estrogen receptor (ER)-positive breast cancer patients receiving tamoxifen monotherapy. The biological mechanisms linking these genes to estrogen signaling and tamoxifen response in breast cancer remain to be determined.


METHODS
In a consecutive series of 148 ER-positive and ER-negative breast cancers, HOXB13, IL17BR, and CHDH gene expression was measured by quantitative real-time PCR and correlated with ER, PR, and HER2 expression. The role of estrogen and ER in the regulation of these three genes was assessed in several ER-positive and ER-negative breast cancer cell lines.


RESULTS
In primary breast tumors, HOXB13 expression correlated negatively, and IL17BR and CHDH expression correlated positively, with ER status, and all three genes exhibited an ER-dependent correlation pattern with HER2 status that differs from PR and PS2, two canonical estrogen-regulated genes. Results using breast cancer cell lines show that these genes are regulated by estradiol in an ER-dependent manner, and that this regulation is abrogated by tamoxifen.


CONCLUSIONS
HOXB13, IL17BR, and CHDH are estrogen-regulated genes, but their pattern of correlation with known positive (ER, PR) and negative (HER2) predictors of tamoxifen response differs from canonical ER signature genes. These results provide a biological rationale for the prognostic utility of these three genes in early-stage ER-positive breast cancer and for their potential to predict anti-estrogen resistance.
Wang
Zuncai
Z
Department of Pathology, Harvard Medical School, Molecular Pathology Research Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
Dahiya
Sonika
S
Provencher
Heather
H
Muir
Beth
B
Carney
Erin
E
Coser
Kathryn
K
Shioda
Toshi
T
Ma
Xiao-Jun
XJ
Sgroi
Dennis C
DC
D001943:Breast Neoplasms / Q000378:metabolism*; D002460:Cell Line; D050545:Choline Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics*; D015331:Cohort Studies; D004967:Estrogens / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D011374:Progesterone / Q000378:metabolism; D011379:Prognosis; D012313:RNA / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D018123:Receptors, Interleukin / Q000096:biosynthesis* / Q000235:genetics*; D053722:Receptors, Interleukin-17; D013629:Tamoxifen / Q000494:pharmacology
D004967:Estrogens; C484414:HOXB13 protein, human; D018398:Homeodomain Proteins; C408922:IL17RB protein, human; D011960:Receptors, Estrogen; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D013629:Tamoxifen; D011374:Progesterone; D012313:RNA; D050545:Choline Dehydrogenase