Are Breast Cancer Metastases Enriched for Stem Cells?
Doreen N Nguyen, Andrea Subhawong, Celina G Kleer, Pedram Argani, Ashley Cimino-Mathews. Johns Hopkins Hospital, Baltimore, MD; University of Michigan, Ann Arbor, MI
Background: The existence of tumor-initiating cells is one hypothesis for tumor initiation and progression. The presence of a stem cell population might imply a major shift in the therapeutic approach to cancer, as current therapies do not target stem cells. This is particularly relevant in breast carcinoma, where no targeted therapies are available for triple negative carcinomas. In addition, few therapeutic options remain for metastatic breast carcinoma resistant to initial therapy. Here, we evaluate the stem cell profile of matched primary (PBC) and metastatic (MBC) breast carcinoma sampled at surgery or at autopsy from 31 different patients.
Design: Tissue microarrays (TMAs) from matched PBCs and surgically-resected MBCs (n=15), as well as from matched PBCs and multiple MBCs sampled at rapid autopsies (n=16), were subjected to immunohistochemistry for ALDH1, EZH2, and CD44/CD24. Tumor cell cytoplasmic ALDH1 and nuclear EZH2 were scored by percentage labeling and intensity, with >1% considered positive. Percentage CD44+/CD24- cells (pink membranous staining) was recorded, with >1% cells considered positive. A 20% change in the percentage labeling for a given stem cell marker between the PBC and MBC was considered an increase or decrease. Carcinomas were subdivided into the following subtypes: luminal (ER+/PR+/Her2-), luminal loss (ER/PR loss from PBC to MBC), Her2 (ER-/PR-/Her2+), and triple negative (TNC) (ER-/PR-/Her2-).
Results: Overall, ALDH1 labeled 8/31 (26%) PBC of MBC; EZH2 labeled all PBC and MBC; and there were CD44+/CD24- cells in 28/31 (90%) PBC or MBC. Forty-two percent MBC showed no change in stem cell marker expression compared to the matched OBC; 23% MBC showed a decrease; 35% MBC showed an increase (see table). There was a trend towards increased stem cell marker expression in the surgically resected MBC, with a decrease in the autopsy MBC.
|Tumor type (n)||No change||Decrease in 1 stem cell marker||Decrease in 2 stem cell markers||Increase in 1 stem cell marker||Increase in 2 stem cell markers|
|Luminal loss (4)||2||1||1||0||0|
|Total (31)||13/31 (42%)||6/31 (19%)||1/31 (3%)||1/31 (3%)||10/31 (32%)|