A new study has demonstrated that direct inhibition of cyclin-dependent kinases may overcome the problem of resistance to anti-estrogen treatment in breast cancer. Cancer is associated with disorders in the regulation of the cell cycle. For example, cellular proliferation, driven by cyclin-dependent kinases (CDKs) and their cyclin partners, is deregulated in cancer. However, if cell cycle regulation is selectively interrupted in cancer cells by interfering with CDK action, the cells will die. Anti-estrogens such as tamoxifen antagonize estrogen-induced ERα transactivation of cyclin D1, resulting in attenuated CDK4/6 activity, p27Kip1-mediated inhibition of CDK2, and growth arrest. However, tamoxifen resistance eventually is acquired by breast cancer cells. Therefore, new strategies are needed to circumvent tamoxifen resistance.

In the study, the authors investigated whether direct inhibition of CDK2 and CDK1 might overcome anti-estrogen resistance. In order to do so, the effects of CDK2/1 siRNA knockdown and purine-based CDK2/1 inhibitors, NU2058 and NU6102, were assessed in anti-estrogen sensitive and resistant breast cancer cells. CDK2 knockdown was found to result in G1 accumulation, while CDK1 depletion resulted in G2/M slowing. Dual CDK1/2 depletion resulted in further G2/M accumulation and cell death in both anti-estrogen sensitive and anti-estrogen resistant cells. These results confirmed CDK2 and CDK1 as targets for breast cancer treatment. While tamoxifen affected only hormone-sensitive breast cancer cells, NU2058 and NU6102 reduced CDK2-mediated processes, leading to cell death in both anti-estrogen sensitive and anti-estrogen resistant breast cancer cells. Both drugs promoted G2/M arrest (reflective of combined CDK2/1 knockdown), with a varying degree of G1 accumulation. The authors conclude that CDK2 and CDK1 inhibitors have therapeutic potential for cancer therapy, and might be useful as an alternative treatment for endocrine-resistant breast cancer.

Foods that protect by influencing cyclin-dependent kinases

The study is part of research that is being performed with the goal of developing effective treatments for hormone receptor positive breast cancer that has become resistant to anti-estrogens such as tamoxifen, as well as for hormone receptor negative breast cancer. The foods listed below, which have been found to be associated with lower risk of breast cancer, are among those which contain compounds that also inhibit CDKs in breast cancer.

Consuming these foods (and limiting or avoiding the foods on our avoid list) is one strategy by which breast cancer survivors and those at high risk for breast cancer might reduce their risk.