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.