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Gene Identification Breast Cancer Chemotherapy Resistance

Some interesting latest findings:
Chemotherapy before surgery is not always effective against some tumors. Now, a study published in Nature Medicine reveals that researchers at Vanderbilt-Ingram Cancer Center (VICC) have identified a gene expression pattern associated to resistance to breast cancer chemotherapy. In addition, the study findings suggest new treatment options for individuals with specific subtypes of breast cancer. 

Of all breast cancer patients that receive chemotherapy to shrink tumors before surgery, around 30% show a complete pathological response, although many still have residual breast cancer after the neoadjuvant chemotherapy (NAC) is completed, meaning that these patients have a higher risk of cancer recurrence and dying from the disease. 

Justin Balko, Pharm.D., Ph.D., postdoctoral fellow in the laboratory of Carlos L. Arteage, M.D., associate director for Clinical Research and director of the Breast Cancer Program at VICC, examined gene expression patterns in 49 breast tumors obtained during surgery and after four months of NAC. 

The researchers identified 244 unique genes linked to high-grade, chemotherapy-resistant tumors. The team then combined these genes, labeled the CLUSTER signature, with previously identified gene signatures so that they could look for distinctive patterns of behavior.

They found that faster tumor cell growth after NAC was strongly associated with low concentrations of dual specificity protein phosphatase 4 (DUSP4). In addition, they found that low DUSP4 was also associated with basal-like breast cancer (BLBC). Compared to other breast cancer subtypes, DUSP4 promoter methylation and gene expression patterns of Ras-ERK pathway activation were also higher in BLBC.

Chemothrapy More Effective When DUAP4 Is Present

According to the researchers, chemotherapy was significantly more effective against cancer cells when DUSP4 was present than when DUSP4 was experimentally deleted. 

Balko explained:


"These data suggest that cells with low DUSP4 expression are enriched during NAC and that low DUSP4 expression in residual resected breast tumors is a potential biomarker for drug resistance and a high likelihood of tumor recurrence."


Furthermore, DUSP4 may be a potential biomarker for response to drugs that inhibit the MEK kinase. The team compared treatment with the chemotherapy drug docetaxel, with and without the MEK inhibitor selumetinib, by using DUSP4-deficient tumors in mice and found that the combination was significantly more effective at eliminating the tumors than docetaxel alone.

Balko said "These data support exploratory clinical trials combining chemotherapy and MEK inhibitors in patients with DUSP-deficient basal-like breast cancer."
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