Basal-like breast cancers arising in women carrying mutations in the BRCA1 gene, encoding the tumor suppressor protein BRCA1, are thought to develop from the mammary stem cell. To explore early cellular changes that occur in BRCA1 mutation carriers, we have prospectively isolated distinct epithelial subpopulations from normal mammary tissue and preneoplastic specimens from individuals heterozygous for a BRCA1 mutation. We describe three epithelial subsets including basal stem/progenitor, luminal progenitor and mature luminal cells. Unexpectedly, we found that breast tissue from BRCA1 mutation carriers harbors an expanded luminal progenitor population that shows factor-independent growth in vitro. Moreover, gene expression profiling revealed that breast tissue heterozygous for a BRCA1 mutation and basal breast tumors were more similar to normal luminal progenitor cells than any other subset, including the stem cell-enriched population. The c-KIT tyrosine kinase receptor (encoded by KIT) emerged as a key marker of luminal progenitor cells and was more highly expressed in BRCA1-associated preneoplastic tissue and tumors. Our findings suggest that an aberrant luminal progenitor population is a target for transformation in BRCA1-associated basal tumors .

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Hormonal cues regulate mammary development, but the consequent transcriptional changes and cell fate decisions are largely undefined. We show that knockout of the prolactin-regulated Ets transcription factor Elf5 prevented formation of the secretory epithelium during pregnancy. Conversely, overexpression of Elf5 in an inducible transgenic model caused alveolar differentiation and milk secretion in virgin mice, disrupting ductal morphogenesis. CD61 + luminal progenitor cells accumulated in Elf5-deficient mammary glands and were diminished in glands with Elf5 overexpression. Thus Elf5 specifies the differentiation of CD61 + progenitors to establish the secretory alveolar lineage during pregnancy, providing a link between prolactin, transcriptional events, and alveolar development.Supplemental material is available at http://www.genesdev.org.

Fig. 1. Immune cell infiltration of lung carcinoma-in-situ lesions. (a-b) Immunohistochemistry images of (a) progressive CIS lesion and (b) regressive CIS lesion with CD4+ cells stained in brown, CD8+ cells in red and FOXP3+ in blue. Immune cells are separately quantified within the CIS lesion and in the surrounding stroma. c) Combined quantitative immunohistochemistry data of CD4, CD8 and FOXP3 staining (n=44; 28 progressive, 16 regressive) with total lymphocyte quantification from H&E images (n=116; 69 progressive, 47 regressive) shown. We observe increased lymphocytes (p=0.023) and CD8+ cells (p=0.037) per unit area of epithelium within regressive CIS lesions compared to progressive. Stromal regions adjacent to CIS lesions showed no significant differences in immune cells between progressive and regressive lesions. p-values are calculated using linear mixed effects models to account for samples from the same patient; *p<0.05. 2 | bioRχiv Pennycuick et al. | Immune surveillance in clinical regression of pre-invasive squamous cell lung cancer .