Researchers discovered a new explanation for why women with estrogen-receptor positive (ER+) breast cancer develop resistance to hormone treatment, and a potential new approach that may overcome the problem. The findings were published in Cell Reports (2015; doi:10.1016/j.celrep.2015.08.050).

Approximately 80% of breast cancers are ER+ and are treated with antiestrogen therapies such as tamoxifen and aromatase inhibitors. But approximately 1 in 5 cases recur within 10 years, and nearly all advanced cases develop resistance, which is why continuing to learn more about how the disease finds ways to survive in some patients and not others is so important.

The study team, based at The University of Manchester’s Institute of Cancer Sciences in the United Kingdom and funded by Breast Cancer Now, found that while short-term treatment with antiestrogen drugs decreased tumor growth, it increased the activity of breast cancer stem cells.

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These stem cells were driven by a signal called NOTCH4. The findings from patient-derived breast cancers in mice and cells grown in the laboratory indicated that it was the presence of NOTCH4 that enabled the cancer stem cells to avoid antiestrogen treatment. In patient tumors, high levels of NOTCH4 before treatment was linked to breast cancer metastasis and worse survival outcomes.

This suggested that resistance to antiestrogen treatment could be overcome by targeting the cancer stem cells with a NOTCH inhibitor, using the cells’ reliance on NOTCH4 as their Achilles’ heel.

“When treating with both tamoxifen and a NOTCH inhibitor, tamoxifen decreased the tumor growth while the NOTCH inhibitor decreased the numbers of breast cancer stem cells that could form new tumors, compared [with] treating with tamoxifen alone,” said study team leader Rob Clarke, PhD, from the Breast Cancer Now Research Unit at The University of Manchester’s Institute of Cancer Sciences.

“This showed us that combining standard hormonal therapies with a NOTCH pathway inhibitor, or other drugs targeting breast cancer stem cells, could improve treatment of ER+ breast cancer patients by preventing relapse due to therapy resistance.”

Importantly, testing for high levels of NOTCH4, or ALDH1, could predict which patient’s breast cancer is likely to be resistant to antiestrogen drugs and which patients would benefit most from antiestrogen therapies and a NOTCH inhibitor combined.

Katie Goates, senior research communications officer at Breast Cancer Now, said: “This is an exciting new explanation as to why women become resistant to tamoxifen and how we could predict and prevent this by testing for, and blocking, NOTCH4 in breast cancer stem cells.

“Validating these findings will take time but general inhibitors of the NOTCH pathway are already being tested in breast cancer clinical trials. The development of resistance to cancer therapies is a huge challenge in the clinic which is why it’s vitally important that we continue to find ways to counteract it, taking us closer towards our ambitious goal of stopping women dying from this devastating disease by 2050.”