Notch Inhibition: A Way Forward for Triple-negative Breast Cancer?

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Since the discovery of the notch pathway 25 years ago, several studies have found a link between different Notch receptors and specific forms of breast cancer, including triple-negative.
Since the discovery of the notch pathway 25 years ago, several studies have found a link between different Notch receptors and specific forms of breast cancer, including triple-negative.

Triple-negative breast cancer (TNBC) continues to be a challenging form of the disease, with limited targeted therapy options. A new review of studies, however, sees a promising avenue in drugs aimed at inhibiting the Notch signaling pathway.

The review of research involving the use of gamma-secretase inhibitors (GSIs) found that they are “preventing metastasis and recurrence and increasing disease-free survival” in a variety of cancers.1 Therefore, the authors concluded, they could be effective against breast cancer, especially in combination with other therapies.

“Overall, targeting the Notch signaling pathway in breast cancer therapy and bidding its downregulation with GSIs looks promising,” they wrote. “Moreover, combined therapy of chemotherapy or radiotherapy with Notch inhibitors also results in a synergistic effect, suggesting Notch inhibitors may improve chemotherapy response. Finally, based on the stratification of patients by Notch activating mutation and amplification, Notch inhibitors combined with chemotherapy or radiotherapy hold great promise for cancer control.”

The connection between the Notch signaling pathway and breast cancer is not new. Notch4 was implicated in a study with mice 25 years ago.2 Since then, several studies found a link between different Notch receptors and specific forms of breast cancer, including triple-negative.

Among them, the review noted, “a study of 200 Greek women from differing breast cancer subtypes, Notch4 mRNA levels were found to be higher in the hormone receptor and HER-2þ breast cancers, whereas Notch1 and Notch3 mRNA levels were higher in TN specimens compared with normal tissue.”

A 2011 study, furthermore, found “evidence for transcriptional regulation of Notch by PEA3 in breast cancer” and that “either PEA3 knockdown or MRK-003 GSI treatment significantly reduced tumor growth.”3

The results, the authors concluded, “demonstrate for the first time that Notch-1 and Notch-4 are novel transcriptional targets of PEA3 in breast cancer cells. Targeting of PEA3 and/or Notch pathways might provide a new therapeutic strategy for triple-negative and possibly other breast cancer subtypes.”

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