Cancer stem cell hypothesis and trastuzumab in HER2-negative tumors.

T rastuzumab (herceptin) is approved for the treatment of breast cancer patients whose tumors express a high level of the drug's target her2/neu. yet at least two retrospective analyses of prospec­ tive trials suggest the drug may also improve survival in women with early breast cancer whose tumors do not overexpress her2/ neu. A plausible mechanism for those con­ troversial observations has been lacking. Now, max Wicha, m.D., and colleagues at the university of michigan think the can­ cer stem cell hypothesis provides adequate explanation, but not everyone is ready to call the case closed so quickly. Wicha, professor of internal medicine and director of the university of michigan Comprehensive Cancer Center in Ann Arbor, is a major proponent of the cancer stem cell hypothesis, which asserts that only a subpopulation of cells within a tumor – referred to as cancer stem cells – can give rise to new tumors or metastases. In the case of her2­positive breast cancer, Wicha and colleagues reported several years ago that her2 appeared to regulate the cancer stem cell popula­ tion. When they engineered several h e r 2 ­ n o r m a l breast cancer cell lines to overex­ press the protein, they found the proportion of cells that express the stem cell marker aldehyde dehy­ drogenase (ALDh) increased. Similarly, the proportion of cells that form spheroids in culture, a trait associated with cancer stem cells, increased. By contrast, when the researchers did the opposite experi­ ment and used trastuzumab to block her2 activity in her2­amplified cell lines, they saw the proportion of ALDh­positive cells dropped. Based on those experiments, the team concluded that trastuzumab's clinical efficacy is due to its ability to reduce the cancer stem cell population in patients with her2­positive tumors. Following on that work and the clinical data hinting that women with her2­negative tumors benefit from adjuvant trastuzumab, Wicha's group started looking for her2­ expressing cells in breast cancer cell lines and tumors clinically characterized as her2 negative. By definition, these tumors express little or no her2 and lack gene amplifica­ tion. however, in some of those cell lines, the team uncovered a subpopulation of cells that expressed her2, and many of those her2­expressing cells also expressed the stem cell marker ALDh. As would have been expected previously, trastuzumab treatment had little effect on the overall cell line population. however, when the team examined the effect of …