Cancer cell of origin: spotlight on luminal progenitors.

Breast cancer is a diverse disease that can be categorized into at least six clinically relevant subtypes based upon molecular gene signatures. The subtypes fit into the broader groupings of either ‘‘basal’’ or ‘‘luminal’’ types because of their molecular similarity to the basal or luminal cells of the normal mammary gland. Thus, basal-type breast cancers express high levels of basal cell markers (cytokeratins 5/6, 14, and 17), whereas luminal-type breast cancers are defined by high expression of luminal cell markers (estrogen receptor alpha, cytokeratins 8/18, and GATA3-binding protein) (Sorlie et al., 2003). Such parallels suggest that the biology of the target cell of oncogenic transformation is echoed in the disease that ensues. Put simply, basal-type breast cancers would seem to arise from transformed mammary basal progenitor cells and luminal-type breast cancers from transformed luminal progenitor cells (Petersen and Polyak, 2010). BRCA1 is a tumor suppressor gene that is often mutated in the germ line, giving rise to greatly elevated risk of developing basal-type breast carcinoma. Previous work had proposed that BRCA1 is an important regulator of mammary stem cell fate and that breast tissues from women with germline BRCA1 mutations had an expansion of BRCA1 mutant mammary stem/progenitor cells (Liu et al., 2008). Furthermore, K14-Cre Brca1 p53 transgenic mice with targeted deletion of BRCA1 to mammary basal cells developed basal-like tumors with features of BRCA1 mutant breast carcinomas (Liu et al., 2007). As such, BRCA1mutant breast cancerwas thought to arise from a basal progenitor/stem cell. A recent flow of papers, however, call this notion into question. In this issue of Cell Stem Cell, Molyneux et al. (2010) took a novel approach to define the cell of origin for BRCA1mutant breast cancer. They analyzed a conditional mousemodel of BRCA1 deficiency, in which Cre recombinase-dependent deletion of exons encoding the C terminus of the BRCA1 protein combined with p53 heterozygosity lead to tumor formation. Pertinent to this model, Cre expression was driven by the Beta lactoglobulin (Blg) promoter and is therefore confined to a subpopulation of mammary epithelial cells. Importantly, the Blg-Cre Brca1 p53 transgenic mice developed mammary tumors that closely resembled human BRCA1 mutant breast cancer. Accordingly, identifying the phenotype of the Blg-positive cells in themousemammary gland should shed light on the cell of origin for BRCA1 basal-type breast carcinoma. To that end, the authors used cellsurface antigen profiles to distinguish threedifferentmammaryepithelial populations. They demonstrated that Blg activity is most evident in a CD24 Sca-1 ER cell population, thusdefininga luminal ER progenitor cell as the cell of origin for BRCA1 mutant basal-like tumors (Figure 1). This novel work is at odds with the previous contention that BRCA1 mutant tumors arise from a mammary basal cell (Liu et al., 2007). To further address these conflicting data, Molyneux et al. (2010) also presents findings directly comparing tumors arising from Blg-Cre Brca1 p53 or an independently constructed line of K14-Cre Brca1 p53 transgenic mice. They arrive at the conclusion that