Embryonic transcription factor upregulation during normal lactation and breast oncogenesis

Abstract

In addition to their physiological role during pregnancy/lactation, mammary stem cells (MaSCs) are primary targets of malignant transformation, giving rise to invasive breast carcinomas. To pinpoint the molecular switches that transform these cells, we must understand the basic machinery that controls their self‐renewal. We non‐invasively accessed lactation‐associated MaSCs via breastmilk. A cell population was identified expressing the pluripotency transcription factors (TFs) Oct4, Sox2 and Nanog, which generated monolayers and spheroids in 2D and 3D culture, respectively, expressing these TFs. Culture in differentiation conditions resulted in differentiation into cells originating from the three germ layers. Examination of normal resting and lactating human breast tissues revealed that these TFs are upregulated during lactation. Lentivirally‐transduced Oct4‐overexpressing mammary cells from the resting gland bypassed cellular senescence and generated subcutaneous tumors with colonization capabilities when injected in nude mice. Examination of different types of breast tumors showed expression of these TFs only in invasive basal tumors with lactating features. It is concluded that these embryonic TFs play important regulatory roles in the normal expansion of the breast during pregnancy/lactation, but also act as oncogenic targets in certain types of breast cancers.Grant Funding Source : Women and Infants Research Foundation (FH); Medela AG (PH); 1R01CA125273 and 3R01CA125273‐03S1 and Department of Defence grant W81XWH‐10‐1‐0265 (PB)