Abstract
Breast cancers with lactating features, some of which are associated with pregnancy and lactation, are often poorly differentiated, lack estrogen receptor, progesterone receptor, and HER2 expression and have high mortality. Very little is known about the molecular mechanisms that drive uncontrolled cell proliferation in these tumors and confer lactating features. We have recently reported expression of OCT4 and associated embryonic stem cell self-renewal genes in the normal lactating breast and breastmilk stem cells (hBSCs). This prompted us to examine OCT4 expression in breast cancers with lactating features and compare it with that observed during normal lactation, using rare specimens of human lactating breast. In accordance with previous literature, the normal resting breast (from non-pregnant, non-lactating women) showed minimal OCT4 nuclear expression (0.9%). However, this increased in the normal lactating breast (11.4%), with further increase in lactating adenomas, lactating carcinomas, and pregnancy-associated breast cancer (30.7–48.3%). OCT4 was expressed in the epithelium and at lower levels in the stroma, and was co-localized with NANOG. Comparison of normal non-tumorigenic hBSCs with OCT4-overexpressing tumorigenic breast cell lines (OTBCs) demonstrated upregulation of OCT4, SOX2, and NANOG in both systems, but OTBCs expressed OCT4 at significantly higher levels than SOX2 and NANOG. Similar to hBSCs, OTBCs displayed multi-lineage differentiation potential, including the ability to differentiate into functional lactocytes synthesizing milk proteins both in vitro and in vivo. Based on these findings, we propose a hypothesis of normal and malignant transformation in the breast, which centers on OCT4 and its associated gene network. Although minimal expression of these embryonic genes can be seen in the breast in its resting state throughout life, a controlled program of upregulation of this gene network may be a potential regulator of the normal remodeling of the breast toward a milk-secretory organ during pregnancy and lactation. Deregulation of this gene network either within or outside pregnancy and lactation may lead to aberrant breast cell proliferation and malignant transformation, suggesting a role of these genes in both normal lactation and breast oncogenesis.
Highlights
Breast cancer associated with pregnancy and lactation (PABC, defined as concurrent with or within 1 year from pregnancy and lactation) is the most frequent malignancy in pregnant women, affecting 1:3000 pregnancies in patients between 32 and 38 years old (Keleher et al, 2002; Gentilini et al, 2005; Barnes and Newman, 2007; Keinan-Boker et al, 2008)
We found that OCT4 is physiologically upregulated during lactation compared with the resting breast, suggesting a potential role of this gene and its associated embryonic stem cells (ESCs) gene network in the normal mammary stem cell (MaSC) selfrenewal that fuels the remodeling of the breast into a fully mature milk-secretory organ
When compared with hBSCs and hESCs, OCT4overexpressing tumorigenic breast cell lines (OTBCs) had markedly higher expression of OCT4 and lower expression of SOX2 and NANOG (Figure 7B). These transcription factor (TF) were expressed at similar levels in each of hESCs and cells from the normal lactating breast, but this balance was completely deregulated in OTBCs (Figure 7B). These results suggest that the distinguishing factor between normal MaSCs and breast cancer stemlike cell (CSC) may be the balance between and expression levels of TFs, which control breast cell self-renewal
Summary
Breast cancer associated with pregnancy and lactation (PABC, defined as concurrent with or within 1 year from pregnancy and lactation) is the most frequent malignancy in pregnant women, affecting 1:3000 pregnancies in patients between 32 and 38 years old (Keleher et al, 2002; Gentilini et al, 2005; Barnes and Newman, 2007; Keinan-Boker et al, 2008) Because this cancer is age-related, its incidence is increasing as many women delay childbearing until later in life (Barnes and Newman, 2007; Keinan-Boker et al, 2008). These cancers often display lactating features, which are sometimes noted in breast tumors that arise outside pregnancy/lactation, and have not yet been molecularly characterized.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
