Targeting c-Src kinase enhances tamoxifen's inhibitory effect on cell growth by modulating expression of cell cycle and survival proteins.
OBJECTIVE
Many studies have implicated the non-receptor tyrosine kinase c-Src in the development and metastatic progression of many types of cancer. In breast cancer, c-Src has been proposed to mediate the actions of estrogen in cell cycle progression.


METHODS
In this study we investigated the interaction between c-Src inhibition and estrogen receptor (ER) function using the ER-positive and tamoxifen-sensitive MCF-7 breast cancer cells.


RESULTS
Pharmacological inhibition of c-Src blocked estrogen-dependent proliferation in MCF-7 cells and enhanced the inhibitory effects of tamoxifen or estrogen-deprivation on cell growth. Maximum inhibition (95%) of cell growth was obtained when tamoxifen and c-Src blockade were combined. Inhibition of c-Src kinase decreased levels of the ER targets c-Myc and cyclin D1 expression but not of Bcl-2. Nevertheless, blocking c-Src kinase in tamoxifen-treated MCF-7 cells led to apoptosis. Inhibition of c-Src kinase altered the ratio of Mcl-1 isoforms in favor of cell death whereas expression of the proapoptotic molecules Bad, Bak, and Bax was not altered. Surprisingly, blocking ER function increased the levels of Bad phosphorylation at serine 112 (BadpS112), an inactive (nonapoptotic) form of Bad. This inactivation of Bad upon ER blockade seemed to depend on c-Src function as chemical inhibition of c-Src kinase reduced BadpS112 levels in cells with impaired ER function but not in estrogen-treated cells.


CONCLUSIONS
These results indicate a crucial role for c-Src kinase in the survival of ER-positive breast cancer cells only when ER function is blocked. Therefore, this study suggests that targeting simultaneously c-Src and ER may effectively inhibit growth of ER-positive breast cancer.
Planas-Silva
Maricarmen D
MD
Department of Pharmacology, Penn State College of Medicine, 500 University Drive, MCH078, Hershey, PA 17033, USA. mcplanas@psu.edu
Hamilton
Kecia N
KN
D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors*; D013629:Tamoxifen / Q000494:pharmacology*
D019253:Proto-Oncogene Proteins c-bcl-2; D013629:Tamoxifen; D019938:Cyclin D1; D016392:Proto-Oncogene Proteins pp60(c-src)