Relevance of breast cancer antiestrogen resistance genes in human breast cancer progression and tamoxifen resistance.
OBJECTIVE
We have previously identified a set of breast cancer antiestrogen resistance (BCAR) genes causing estrogen independence and tamoxifen resistance in vitro using a functional genetic screen. Here, we explored whether these BCAR genes provide predictive value for tamoxifen resistance and prognostic information for tumor aggressiveness in breast cancer patients.


METHODS
mRNA levels of 10 BCAR genes (AKT1, AKT2, BCAR1, BCAR3, EGFR, ERBB2, GRB7, SRC, TLE3, and TRERF1) were measured in estrogen receptor-positive breast tumors using quantitative reverse-transcriptase polymerase chain reaction. Normalized mRNA levels were evaluated for association with progression-free survival (PFS) in 242 patients receiving tamoxifen as first-line monotherapy for recurrent disease, and with distant metastasis-free survival (MFS) in 413 lymph node-negative (LNN) primary breast cancer patients who did not receive systemic adjuvant therapy.


RESULTS
Concerning tamoxifen resistance, BCAR3, ERBB2, GRB7, and TLE3 mRNA levels were predictive for PFS, independent of traditional predictive factors. By combining GRB7 (or ERBB2) and TLE3 mRNA levels, patients could be classified in three subgroups with distinct PFS. For the evaluation of tumor aggressiveness, AKT2, EGFR, and TRERF1 mRNA levels were all significantly associated with MFS, independent of traditional prognostic factors. Using the combined AKT2 and EGFR mRNA status, four prognostic groups were identified with different MFS outcomes.


CONCLUSIONS
The majority of BCAR genes, which were revealed to confer tamoxifen resistance and estrogen independence in vitro by functional screening, have clinical relevance, and associate with tamoxifen resistance and/or tumor aggressiveness in breast cancer patients.
van Agthoven
Ton
T
Department of Pathology, Cancer Genomics Center, Josephine Nefkens Institute, Erasmus MC-University Medical Center Rotterdam, Rotterdam, the Netherlands.
Sieuwerts
Anieta M
AM
Meijer-van Gelder
Marion E
ME
Look
Maxime P
MP
Smid
Marcel
M
Veldscholte
Jos
J
Sleijfer
Stefan
S
Foekens
John A
JA
Dorssers
Lambert C J
LC
D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D013629:Tamoxifen / Q000627:therapeutic use*
D018931:Antineoplastic Agents, Hormonal; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D013629:Tamoxifen