Researchers have discovered how tamoxifen-resistant breast cancer cells grow and proliferate. This understanding may offer a novel targeted therapy for tamoxifen-resistant breast cancer.

An estimated 230,000 new cases of breast cancer are expected in the United States in 2012, along with 40,000 deaths from the disease. More than two-thirds of cases of breast cancer have high levels of the estrogen receptor, and so they can be treated with tamoxifen.

Tamoxifen has improved the disease-free survival of those with estrogen receptor-positive breast cancer by 50%. But, 30% to 40% of patients taking tamoxifen become resistant to it after approximately 5 years, and then those patients face limited options. When tamoxifen shuts down the pathway activated by estrogen, the growth of breast cancer cells can be promoted by the hedgehog and PI3K/AKT signaling pathways. When the hedgehog pathway is activated, tamoxifen treatment is ineffective, so the tumor can grow and progress. Currently, chemotherapy is used to treat hormone-resistant breast cancer, but it has significant side effects.

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The researchers analyzed more than 300 human tumors and found that those tumors with an activated hedgehog pathway had a worse prognosis regarding disease-free survival and overall survival. Also, they demonstrated that the experimental drug vismodegib, which blocks the hedgehog pathway, inhibits the growth of tamoxifen-resistant human breast tumors in an animal model. Vismodegib is in clinical trials for other types of cancer.

“Our findings suggest that 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 Ohio State University Comprehensive Cancer Center.

Their current publication describes a link between hedgehog signaling and the PI3K/AKT pathway. Treatments that target the hedgehog pathway alone or in combination with the PI3K/AKT pathway could be novel therapeutic options for tamoxifen-resistant breast cancer.

“Our next step is to organize a clinical trial to evaluate vismodegib in patients with tamoxifen-resistant breast cancer,” Ramaswamy says.

This research was published in Cancer Research (2012; doi:10.1158/0008-5472.CAN-12-1248).