Dramatic new approach: using Src inhibitors to turn ER- into ER+ tumors

[Lani]

It turns out ER- tumors do have ER mRNA (the message necessary to make the Estrogen receptor) just as ER+ tumors do. However they have elevated levels of Src, which serves to dissolve ER receptors (via proteolysis). It had previously been shown that Src inhibitors are effective in her2+ bc (will reread that article)--now it is shown that using a Src inhibitor will turn ER- into ER+ tumors.

J Clin Invest. 2007 Jul 12; [Epub ahead of print]Links
Src promotes estrogen-dependent estrogen receptor alpha proteolysis in human breast cancer.

Chu I, Arnaout A, Loiseau S, Sun J, Seth A, McMahon C, Chun K, Hennessy B, Mills GB, Nawaz Z, Slingerland JM.
Braman Family Breast Cancer Institute and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA. Department of Medical Biophysics, Department of Surgery, and Department of Pathobiology and Laboratory Medicine, University of Toronto, Toronto, Ontario, Canada. Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Estrogen drives both transcriptional activation and proteolysis of estrogen receptor alpha (ERalpha; encoded by ESR1). Here we observed variable and overlapping ESR1 mRNA levels in 200 ERalpha-negative and 50 ERalpha-positive primary breast cancers examined, which suggests important posttranscriptional ERalpha regulation. Our results indicate that Src cooperates with estrogen to activate ERalpha proteolysis. Inducible Src stimulated ligand-activated ERalpha transcriptional activity and reduced ERalpha t(1/2). Src and ERalpha levels were inversely correlated in primary breast cancers. ERalpha-negative primary breast cancers and cell lines showed increased Src levels and/or activity compared with ERalpha-positive cancers and cells. ERalpha t(1/2) was reduced in ERalpha-negative cell lines. In both ERalpha-positive and -negative cell lines, both proteasome and Src inhibitors increased ERalpha levels. Src inhibition impaired ligand-activated ERalpha ubiquitylation and increased ERalpha levels. Src siRNA impaired ligand-activated ERalpha loss in BT-20 cells. Pretreatment with Src increased ERalpha ubiquitylation and degradation in vitro. These findings provide what we believe to be a novel link between Src activation and ERalpha proteolysis and support a model whereby crosstalk between liganded ERalpha and Src drives ERalpha transcriptional activity and targets ERalpha for ubiquitin-dependent proteolysis. Oncogenic Src activation may promote not only proliferation, but also estrogen-activated ERalpha loss in a subset of ERalpha-negative breast cancers, altering prognosis and response to therapy.
PMID: 17627304 [PubMed - as supplied by publisher]

[Lani]

Up to one-third of primary breast cancers show HER2/
erbB-2 amplification, and a similar proportion has
increased EGFR expression. Both are strongly associated
with ER?– status (52, 53). Transfection of either EGFR or
activated Her2 can reduce ER? levels in MCF-7 cells, and
this has been attributed to MAPK activation (54). How-
ever, both of these receptors activate Src. In breast cancer
cells, cSrc binds phosphorylated Her2 or EGFR, promot-
ing synergistic activation to stimulate breast cancer cell
proliferation and survival (49). Indeed, Src inhibitors
impair Her2- and EGFR-driven mitogenesis (49, 55). Src is
also transiently recruited to and activated by estrogen-bound ER?,
leading to MAPK activation (22–25).

[Hopeful]

that discusses Src as a therapeutic target for both hormone and growth factor resistant bc: http://erc.endocrinologyjournals.org...pplement_1/S53

Hopeful