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Another Feather In The Cap Of The Breast Cancer Oncogene IKKε

There has been considerable progress in the treatment of breast cancer. Advances in diagnosis, surgery, radiotherapy, and targeted chemotherapy have transformed the lives of many breast cancer sufferers. However, these benefits have certainly not been universally shared. Breast cancer recurrence and the complications associated with the spread of tumor cells to other organs still remain areas of unmet clinical needs.

Breast cancer cells preferentially metastasize to bone, and approximately 65% of advanced breast cancer patients suffer from skeletal complications such as bone pain, loss, and fractures. The war on breast cancer metastasis has many fronts, and the development of cancer-induced bone disease relies on a series of complex, interrelated events. Conventional wisdom suggests that the homing of breast cancer cells to the skeleton and the ability of a small colony of these cells to expand and disrupt the finely-tuned bone remodeling cycle of repair and renewal are key to the development of secondary breast cancer in bone. One physiological process implicated in the regulation of these events is inflammation.

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In 2007, a study published in the scientific journal Cell identified IKKε (IKK-Epsilon) as one of the genes that transform healthy breast cells into tumor cells (also known as oncogenes). Members of the IKK family are known to regulate inflammation-related bone damage by promoting the activity of osteoclasts (bone-destroying cells). Previous studies carried by our laboratory and others have shown that inhibition of IKK activity in mice reduced bone damage caused by inflammation, osteoporosis, and breast cancer cell growth in bone. These findings, together with the identification of IKKε as a breast cancer oncogene, sparked new appreciation and rekindled our interest in the role of IKK in breast cancer bone metastasis.

In our recent paper published in the cancer journal Cancer Letters in 2019, we focused on answering two important questions: does the treatment of mice with an IKKε inhibitor — alone or in combination with chemotherapy — reduce the early metastatic spread of breast cancer cells in the body after removal of the primary tumor? And if yes, would inhibition of IKKε activity in metastatic breast cancer cells alone or in both breast cancer and bone cells protect against bone damage in mice?

We first observed that IKKε inhibition in human breast cancer cells alone was sufficient to reduce their ability to increase the number of osteoclasts in a Petri dish and to grow in the skeleton of mice, suggesting that IKKε is implicated in the regulation of breast cancer – bone cell interactions. Consistent with this, administration of a verified IKKε inhibitor called Amlexanox reduced tumor growth following intra-tibial injection of “bony” breast cancer cells in mice.

In contrast, treatment of mice with Amlexanox alone failed to reduce the spread of breast cancer cells from mouse mammary glands after the removal of the tumor. Of direct clinical relevance, treatment of mice with Amlexanox enhanced the anti-tumor and anti-metastatic effects of Docetaxel (an FDA-approved chemotherapeutic agent used in breast cancer patients). Of significant importance to us was the observation that combined administration of Amlexanox and Docetaxel prolonged the survival of mice after the surgical removal of the primary tumors. These findings were exciting, as they lend further support to the notion that cancer treatments aimed at blocking more than one aspect of the disease may have added benefits to chemotherapy alone in terms of clinical outcomes.

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Another potential issue of equal importance — but not addressed in our study — is the effects of these drugs on immunity. It is a known fact that IKK activation by inflammatory cytokines secreted by immune cells fights infection and suppresses tumor growth in mice. Thus, it is not unreasonable to speculate that the anti-inflammatory action of IKKε inhibitors may compromise some cancer patients’ immune response. These issues provide a powerful case for testing of staged and timed dosing of anti-inflammatory agents such as IKKε inhibitors — alone and in combination with chemotherapy or immunotherapy — in preclinical models of all stages of breast cancer.

Whilst more research in this area is still needed, this much is certain: a treatment strategy aimed at suppressing inflammation, protecting against cancer-related bone damage, and reducing the excessive activity of oncogenes is likely to be superior to bone-targeted therapies such as Bisphosphonates (Bonefos, Bondronat, and Zometa) and the human antibody Denosumab in the management of various aspects of metastatic breast cancer.

These findings are described in the article entitled Pharmacological inhibition of the IKKε/TBK-1 axis potentiates the anti-tumour and anti-metastatic effects of Docetaxel in mouse models of breast cancer, recently published in the journal Cancer Letters. This work was conducted by Ryan T. Bishop, Silvia Marino, Daniëlle de Ridder, Richard J Allen, Diane V. Lefley, Ning Wang, Penelope D. Ottewell and Aymen I. Idris from the University of Sheffield, UK, in collaboration with Dr. Andrew H. Sims from the University of Edinburgh, UK. This research was funded by Breast Cancer Now.

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