Xu et al. have discovered that two sustained signals combine to support milk production by mammary cells.
In vivo, mammary epithelial cells synthesize milk proteins when stimulated by the hormone prolactin. Yet, when these cells are cultured on flat, plastic dishes they do not make milk proteins even when prolactin is added to the cultures. The authors found that the cells on plastic became polarized with separate apical and basolateral surfaces. The prolactin receptor is present on the cells, but is localized on their basolateral side—attached to the dish—and thus cannot be accessed by prolactin applied to the apical surface.
Xu et al. showed that if prolactin was applied basolaterally to cells on plastic it could activate STAT5, the transcription factor that controls the expression of milk proteins—but this signal was transient and insufficient to support milk protein production. A second signal was required to achieve the sustained STAT5 activation and subsequent chromatin rearrangements that make milk genes accessible for transcription. This signal was supplied when the cells were grown in a laminin-111–rich gel: under these conditions, cells form into hollow spheroids called acini with their prolactin receptor exposed to the exterior.
Xu et al. showed that laminin-111 signaling (via a laminin receptor) synergizes with the prolactin signal to sustain STAT5 activation, though exactly how these two signals come together is so far unknown.