Unsuspected protein determines resistance to breast cancer treatment

An innovative research approach has identified a previously unsuspected protein as a key player in the resistance to particular forms of breast cancer therapy. The study, published by Cell Press in the February issue of Cancer Cell, significantly advances the understanding of the molecular response to breast cancer therapies that target estrogen signaling.

Most breast tumors express estrogen receptor and are dependent on estrogen signaling. Drugs that target this characteristic, such as tamoxifen, have had a major impact on breast cancer therapy as they interfere with the ability of estrogen to activate its receptor and, as a result, limit cellular proliferation.

However, although widely used, the effectiveness of tamoxifen is profoundly limited by the development of drug resistance. “All patients with metastatic disease and 40% of early-stage breast cancer patients treated with tamoxifen eventually relapse with tamoxifen-resistant disease,” explains lead author Professor Alan Ashworth from the Breakthrough Breast Cancer Research Centre at The Institute of Cancer Research in London, England.

To develop a better understanding of the molecular events that contribute to the development of treatment resistance, Prof. Ashworth, Dr. Christopher J. Lord and colleagues used a sophisticated and highly selective loss-of-function RNA interference screening method to identify genes that, when silenced, cause tamoxifen resistance. The researchers identified Cyclin-Dependent Kinase 10 (CDK10) as a critical component of the response to tamoxifen and other therapies that target estrogen signaling.

Examination of signaling molecules downstream of CDK10 led the authors to propose that CDK10 normally represses the ETS2 transcription factor and that the loss of CDK10 expression results in relief of ETS2 repression and upregulation of c-RAF transcription. Enhanced c-RAF activation results in activation of mitogen-activated protein kinase and increased cyclin D1 expression, both previously linked to tamoxifen resistance. Together, these events link tamoxifen with a loss of reliance on estrogen signaling.

Importantly, the researchers also found that in patients treated with tamoxifen, drug resistance occurred significantly earlier in those with tumors that express low levels of CDK10. Furthermore, methylation of the CDK10 gene also correlated with resistance. Methylation of genes is well-established as a means by which gene expression can be controlled and suggests a mechanism that could switch off CDK10 expression in tumor cells.

“Drug resistance is a serious problem for women with breast cancer. It’s devastating for a patient to see their cancer return because of resistance, especially after enduring a long course of treatment and after a long period of remission. Through this work, we’ve identified some of the factors that control this effect and in the future we may be able to use this information to decide which treatments to give to patients to avoid resistance,” says Prof. Ashworth.

Source: Cell Press

Related stories:

Overweight, insulin resistant women at greater risk of advanced breast cancer diagnosis, says study
Women who have risk factors commonly associated with Type 2 diabetes also have much greater odds of being diagnosed with an advanced breast cancer, according to research to be presented today.
New cancer treatment targets both tumor cells and blood vessels
MU researchers develop nontoxic treatment that has broad anti-cancer potential
It takes more than one punch to fight tumors. Often, tumors have more than one way of surviving, and attacking the tumor alone is not enough. Now, in a new study, University of Missouri researchers have developed a new non-toxic treatment that effectively reduces breast cancer cells, by combining a small molecular drug that targets tumor cells with an antibody that causes selective shutdown of tumor blood vessels.
Diabetes drug slows early-onset puberty in girls
In young girls at risk of early puberty and insulin resistance, the diabetes drug metformin delayed the onset of menstruation and decreased the development of insulin resistance, a risk factor for type 2 diabetes, according to a new study. The results were presented Monday, June 16, at The Endocrine Society's 90th Annual Meeting in San Francisco.
Age at puberty linked to mother's prenatal diet
A high-fat diet during pregnancy and nursing may lead to the child having an early onset of puberty and subsequent adulthood obesity, according to a new animal study. The results were presented Monday, June 16, at The Endocrine Society's 90th Annual Meeting in San Francisco.
Overcoming Drug Resistance—Nanoparticles Trigger Built-In Cell-Death Signal
One of the most vexing problems in treating cancer is the propensity of tumors to develop resistance to a wide range of anticancer drugs. Over 70 percent of ovarian cancer patients, for example, have drug-resistant tumors at the time of their initial diagnosis, and virtually all patients who relapse have drug-resistant tumors.
Metformin increases pathologic complete response rates in breast cancer patients with diabetes
Metformin, the common first-line drug for type 2 diabetes, may be effective in increasing pathologic complete response rates in diabetic women with early stage breast cancer who took the drug during chemotherapy prior to having surgery, paving the way for further research of the drug as a potential cancer therapy, according to researchers at The University of Texas M. D. Anderson Cancer Center.
Protein predicts Gleevec resistance in gastrointestinal tumors
Excess amounts of a protein called IGF-1R in patients with gastrointestinal stromal tumors (GISTs) could indicate that the patient would be less responsive to the drug imatinib mesylate (known as Gleevec), according to Andrew K. Godwin, Ph.D., a researcher at the Fox Chase Cancer Center in Philadelphia.
Coming soon: Cell therapies for diabetes, cancer?
Therapies using stem cell transplants are advancing promising treatments for such conditions as Alzheimer’s Disease, neurological diseases and spinal cord injury, and heart disease. Now, scientists think that stem cell transplants may ultimately benefit those who suffer from diabetes or cancer.

News discussion:

Medicine & Health news