Abstract
BackgroundAlthough human breast development is mediated by hormonal and non-hormonal means, the mechanisms that regulate breast progenitor cell activity remain to be clarified. This limited understanding of breast progenitor cells has been due in part to the lack of appropriate model systems to detect and characterize their properties.MethodsTo examine the effects of WNT signaling and TBX3 expression on progenitor activity in the breast, primary human mammary epithelial cells (MEC) were isolated from reduction mammoplasty tissues and transduced with lentivirus to overexpress WNT1 or TBX3 or reduce expression of their cognate receptors using shRNA. Changes in progenitor activity were quantified using characterized assays. We identified WNT family members expressed by cell populations within the epithelium and assessed alterations in expression of WNT family ligands by MECs in response to TBX3 overexpression and treatment with estrogen and progesterone.ResultsGrowth of MECs on collagen gels resulted in the formation of distinct luminal acinar and basal ductal colonies. Overexpression of TBX3 in MECs resulted in increased ductal colonies, while shTBX3 expression diminished both colony types. Increased WNT1 expression led to enhanced acinar colony formation, shLRP6 decreased both types of colonies. Estrogen stimulated the formation of acinar colonies in control MEC, but not shLRP6 MEC. Formation of ductal colonies was enhanced in response to progesterone. However, while shLRP6 decreased MEC responsiveness to progesterone, shTBX3 expression did not alter this response.ConclusionsWe identified two phenotypically distinguishable lineage-committed progenitor cells that contribute to different structural elements and are regulated via hormonal and non-hormonal mechanisms. WNT signaling regulates both types of progenitor activity. Progesterone favors the expansion of ductal progenitor cells, while estrogen stimulates the expansion of acinar progenitor cells. Paracrine WNT signaling is stimulated by estrogen and progesterone, while autocrine WNT signaling is induced by the embryonic T-box transcription factor TBX3.
Highlights
The regenerative capacity of the mammary gland is driven by a complex cellular hierarchy that switches from multipotent stem cells during embryogenesis to hormone sensitive stem/progenitor cells shortly after birth [1,2,3,4,5]
TBX3 enhances progenitor activity in adult human breast epithelial cells TBX3 expression is necessary for breast organogenesis and its aberrant expression has been identified in breast cancers, yet little is known about its function in epithelial cells of the adult human breast
Primary mammary epithelial cells (MEC) and MCF10A cells were transduced with full length human TBX3 or with short hairpins targeting TBX3
Summary
The regenerative capacity of the mammary gland is driven by a complex cellular hierarchy that switches from multipotent stem cells during embryogenesis to hormone sensitive stem/progenitor cells shortly after birth [1,2,3,4,5]. Since adult Tbx heterozygous mice have reduced ductal branching in all 5 pairs of mammary glands [23], it is likely that TBX3 is necessary for mammary stem/progenitor cell proliferation following embryonic development. TBX3 is necessary for the maintenance of stem cell self-renewal, cell-fate determination and organogenesis (for review, [25,26,27]) Together this suggests that TBX3 may play a role in the regulation of stem cell activity within the normal mammary epithelium. Human breast development is mediated by hormonal and non-hormonal means, the mechanisms that regulate breast progenitor cell activity remain to be clarified. This limited understanding of breast progenitor cells has been due in part to the lack of appropriate model systems to detect and characterize their properties
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