Hedgehog pathway key in tamoxifen-resistant breast CA

November 6, 2012
Hedgehog pathway key in tamoxifen-resistant breast CA
Noncanonical Hedgehog signaling is activated in tamoxifen-resistant tumors, and the phosphoinositide 3-kinase inhibitor/protein kinase B pathway plays a key role protecting Hedgehog signaling molecules, according to a study published in the Oct. 1 issue of Cancer Research.

(HealthDay)—Noncanonical Hedgehog (Hh) signaling is activated in tamoxifen-resistant tumors, and the phosphoinositide 3-kinase inhibitor/protein kinase B (PI3K/AKT) pathway plays a key role protecting Hh signaling molecules, according to a study published in the Oct. 1 issue of Cancer Research.

Noting that patients with resistance to endocrine therapy have poor outcomes, Bhuvaneswari Ramaswamy, M.D., from The Ohio State University in Columbus, and colleagues examined the role of Hh signaling in tamoxifen-resistant tumors.

The researchers found that the Hh signaling pathway was activated in tamoxifen-resistant tumors and that the / protected key components of the Hh signaling pathway from proteasomal degradation. In tamoxifen-resistant MCF-7 and T47D cells, the levels of Hh signaling molecules SMO and GLI1 and their targets were found to be significantly elevated. Serial passage of the in mice led to , which spread to distant organs, and simultaneous increases in Hh marker expression. SMO or GLI1 depletion mediated by RNAi correlated with reduced proliferation, clonogenic survival, and delayed transition from G1 to S. Treatment of resistant cells with PI3K inhibitors resulted in reduced SMO and GLI1 protein levels and activity, while blocking GSK3β and proteasomal degradation rescued these levels and activity. Anti-Hh compound GDC-0449 treatment of tamoxifen-resistant xenografts correlated with blocked tumor growth in mice. In a cohort of 315 patients with breast cancer, high GLI1 expression was inversely associated with disease-free and overall survival.

"In summary, our results describe a signaling event linking PI3K/AKT pathway with Hh signaling that promotes tamoxifen resistance," the authors write. "Targeting Hh pathway alone or in combination with PI3K/AKT pathway could therefore be a novel therapeutic option in treating endocrine-resistant breast cancer."

More information: Abstract
Full Text (subscription or payment may be required)

Related Stories

Combination therapies for drug-resistant cancers

October 10, 2011

Some cancers can be effectively treated with drugs inhibiting proteins known as receptor tyrosine kinases, but not those cancers caused by mutations in the KRAS gene. A team of researchers led by Jeffrey Engelman, at Massachusetts ...

Recommended for you

New treatment options for a fatal leukemia

July 27, 2015

In industrialized countries like in Europe, acute lymphoblastic leukemia is the most common form of cancer in children. An international research consortium lead by pediatric oncologists from the Universities of Zurich and ...

Modified DNA building blocks are cancer's Achilles heel

July 22, 2015

In studying how cells recycle the building blocks of DNA, Ludwig Cancer Research scientists have discovered a potential therapeutic strategy for cancer. They found that normal cells have highly selective mechanisms to ensure ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.