Selective recruitment of breast cancer anti-estrogen resistance genes and relevance for breast cancer progression and tamoxifen therapy response.
Although endocrine treatment of breast cancer is effective and common practice, in advanced disease the development of resistance is nearly inevitable. To get more insight into individual genes that account for resistance against hormonal agents, we have executed functional genetic screens and subsequently evaluated the clinical relevance of several identified genes with respect to tumor aggressiveness and tamoxifen resistance in estrogen receptor-positive patients. Estrogen-dependent human breast cancer cells were transduced with different retroviral cDNA expression libraries and subjected to selective cultures with various anti-estrogens. From a total of 264 resistant cell clones, 132 different genes were recovered by PCR. By applying stringent selection criteria, we identified 15 breast cancer anti-estrogen resistance (BCAR) genes individually yielding resistance. BCAR genes were recovered with differential frequencies for the diverse culture conditions and anti-estrogen drugs. Analysis of the relation of BCAR genes (EIF1, FBXL10, HRAS, NRG1, PDGFRA, PDGFRB, RAD21, and RAF1) with tamoxifen treatment in patients with advanced disease showed significant association with clinical benefit and progression-free survival for EIF1 and PDGFRA mRNA levels. Furthermore, PDGFRA and HRAS mRNA levels were significantly associated with tumor aggressiveness in lymph node-negative patients who had not received adjuvant systemic therapy. In conclusion, our functional genetic screens showed that BCAR genes differ in their ability to confer resistance towards distinct anti-estrogens. Based on the clinical relevance of several BCAR genes, further studies are warranted to characterize the underlying mechanisms, which may ultimately lead to the development of novel treatments and more individualized management of breast cancer patients.
van Agthoven
Ton
T
Department of Pathology, Josephine Nefkens Institute, Erasmus MC - University Medical Center Rotterdam, Be432, Erasmus MC. PO Box 2040, 3000 CA Rotterdam, The Netherlands.
Sieuwerts
Anieta M
AM
Meijer
Danielle
D
Meijer-van Gelder
Marion E
ME
van Agthoven
Thecla L A
TL
Sarwari
Roya
R
Sleijfer
Stefan
S
Foekens
John A
JA
Dorssers
Lambert C J
LC
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D050719:Crk-Associated Substrate Protein / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D004965:Estrogen Antagonists / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005820:Genetic Testing; D020662:Guanine Nucleotide Exchange Factors; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D012189:Retrospective Studies; D013379:Substrate Specificity; D013629:Tamoxifen / Q000627:therapeutic use*
D048868:Adaptor Proteins, Signal Transducing; D018931:Antineoplastic Agents, Hormonal; C493841:BCAR1 protein, human; C118588:BCAR3 protein, human; D054316:Biomarkers, Pharmacological; D050719:Crk-Associated Substrate Protein; D004965:Estrogen Antagonists; D020662:Guanine Nucleotide Exchange Factors; D013629:Tamoxifen