Cooperative action of tamoxifen and c-Src inhibition in preventing the growth of estrogen receptor-positive human breast cancer cells.
It has long been appreciated that estrogenic signaling contributes to breast cancer progression. c-Src is also required for a number of processes involved in tumor progression and metastasis. We have previously identified the K303R mutant estrogen receptor alpha (ERalpha) that confers hypersensitivity to low levels of estrogen. Because ERalpha and c-Src have been shown to interact in a number of different systems, we wanted to evaluate the role of c-Src kinase in estrogen-stimulated growth and survival of ERalpha-positive breast cancer cells. MCF-7 cells stably expressing the mutant receptor showed increased c-Src kinase activity and c-Src tyrosine phosphorylation when compared with wild-type ERalpha-expressing cells. A c-Src inhibitor, AZD0530, was used to analyze the biological effects of pharmacologically inhibiting c-Src kinase activity. MCF-7 cells showed an anchorage-dependent growth IC50 of 0.47 micromol/L, which was increased 4-fold in the presence of estrogen. In contrast, cells stably expressing the mutant ERalpha had an elevated IC50 that was only increased 1.4-fold by estrogen stimulation. The c-Src inhibitor effectively inhibited the anchorage-independent growth of both of these cells, and estrogen was able to reverse these effects. When cells were treated with suboptimal concentrations of c-Src inhibitor and tamoxifen, synergistic inhibition was observed, suggesting a cooperative interaction between c-Src and ERalpha. These data clearly show an important role for ERalpha and estrogen signaling in c-Src-mediated breast cancer cell growth and survival. Here, we show that c-Src inhibition is blocked by estrogen signaling; thus, the therapeutic use of c-Src inhibitors may require inhibition of ERalpha in estrogen-dependent breast cancer.
Herynk
Matthew H
MH
Breast Center, Baylor College of Medicine, One Baylor Plaza, Mailstop 600, Houston, TX 77030, USA.
Beyer
Amanda R
AR
Cui
Yukun
Y
Weiss
Heidi
H
Anderson
Elizabeth
E
Green
Tim P
TP
Fuqua
Suzanne A W
SA
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D052117:Benzodioxoles / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D000081247:CSK Tyrosine-Protein Kinase; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D047628:Estrogen Receptor alpha / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology*; D019061:src-Family Kinases
D052117:Benzodioxoles; D047628:Estrogen Receptor alpha; D004967:Estrogens; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D013629:Tamoxifen; C515233:saracatinib; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human