Two genes associated with aggressive breast cancer are linked to a key property of mammary stem cell function, according to researchers at the University of Michigan.
The genes, PTEN and HER2, both are involved in the biochemical pathways that mediate stem cell self-renewal, a defining property of stem cells.
According to the researchers, understanding the pathways that regulate stem cell self-renewal is important in developing therapeutics that target the tumor stem cell pool. These genes might also become targets of interest in the treatment of tumors resistant to the drug Herceptin.
“We now believe that our results show further evidence that breast cancer arises from signaling errors in the biochemical pathways that control mammary stem cell self-renewal” said Hasan Korkaya, D.V.M., Ph.D., a research fellow at the University of Michigan?s Comprehensive Cancer Center. “Since only stem cells have the ability to self-renew, deregulation of either PTEN or HER2 expands the stem cell populations with self-renewing ability.”
According to Korkaya, cells with deregulated ? or increased ? self-renewing ability will then initiate and maintain tumors that are resistant to current therapies.
The two genes appear to influence stem cell self-renewal by controlling two different arms of the pathway, says Korkaya. In breast cancer, the loss of PTEN is linked to nearly a quarter of all cases, while the overproduction of HER2 is associated with nearly 40 percent of all cases. Patients with a combined defect of PTEN loss and HER2 amplification represent worse prognosis than either defect alone.
To replicate this clinical phenomenon and study the link between stem cell self-renewal and tumorigenesis, the researchers altered the expression of the two genes in a line of human breast carcinoma cells. In experimental settings, their results confirmed this clinical data that either defect increases stem cell population by three to five times. Furthermore, Korkaya observed an additive effect and an approximate 10-fold increase in stem cell population when they created a cell line with deleted PTEN and HER2 overexpression. Another property of aggressive tumors is metastasis; the team also found that these cells had increased invasive capacity in a matrigel invasion assay.
“In general, tumors are heterogeneous including stem and non-stem cell populations in a given malignancy,” Korkaya said. “If the stem cells acquired mutations in their self-renewing pathways, they will then begin reproducing at an accelerated rate, leading to a particularly aggressive form of cancer.”
The researchers believe further studies will identify new biomarkers that will enable physicians to clinically screen patients for mammary stem cells and provide specific treatments designed to target these cells.