Hedgehog Hunting

A Possible Therapy for Tamoxifen-Resistant Breast Cancer

Bhuvana RamaswamySarmila MajumderResearchers at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James) have discovered how tamoxifen-resistant breast cancer cells grow and proliferate. The study suggests an experimental agent might offer a targeted therapy for tamoxifen-resistant breast cancer.

Like a second door that opens after the first door closes, a signaling pathway called hedgehog (Hhg) can promote the growth of breast-cancer cells after tamoxifen shuts down the pathway activated by the hormone estrogen. A second signaling pathway, called PI3K/AKT, is also involved.

Activation of the Hhg pathway renders tamoxifen treatment ineffective and enables the tumor to resume its growth and progression. As part of the study, the researchers analyzed more than 300 human tumors and found that those with an activated Hhg pathway had a worse prognosis.

Finally, the researchers showed that an experimental drug called vismodegib, which blocks the Hhg pathway, inhibits the growth of tamoxifen-resistant human breast tumors in an animal model. The drug is in clinical trials testing for other types of cancer.

Chemotherapy is currently used to treat hormone-resistant breast cancers, but it causes significant side effects. This study has identified targeted therapies that could be an alternative to chemotherapy for these resistant tumors.

“Our findings suggest we can target this pathway in patients with estrogen-receptor breast cancers who have failed tamoxifen therapy,” says first author Bhuvaneswari Ramaswamy, MD, a medical oncologist specializing in breast cancer at the OSUCCC – James.

“We describe a link between the hedgehog signaling pathway, which promotes tamoxifen resistance, and the PI3K/AKT pathway,” adds principal investigator Sarmila Majumder, PhD, a research assistant professor in Molecular and Cellular Biochemistry at Ohio State and member of the OSUCCC – James. “Targeting the hedgehog pathway alone or in combination with the PI3K/AKT pathway could be a novel therapeutic option for treating tamoxifen-resistant breast cancer.”

Published in the journal Cancer Research.

Funding from NIH/National Cancer Institute grants CA137567 and CA133250, and a Pelotonia Idea Grant supported this research.

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