During pregnancy, a subgroup of cells in the mammary gland begins to rapidly proliferate and to differentiate into milk-producing cells. These changes occur, in part, as a result of stimulation by the hormone prolactin, which activates the STAT5 transcription factor, a key activator of milk protein-encoding genes. However, a number of other signaling pathways are also involved, among them the neuregulins (NRGs), which bind to and activate ErbB4, a member of the epidermal growth factor receptor (EGFR) family. Upon NRG binding, ErbB4 forms a dimer with a second EGFR family member, and a frequent partner is ErbB3. This led Vanderbilt Basic Sciences investigator Rebecca Cook and her laboratory to investigate a possible role for ErbB3 in mammary gland differentiation during pregnancy. They created a genetically engineered mouse model that selectively lacks ErbB3 expression in the mammary gland. They found reduced proliferation and increased death of cells in the gland during mid-pregnancy, as compared to what is observed in the glands of wild-type mice. As a result, fewer milk-producing cells formed, and offspring of the ErbB3-deficient mice failed to gain weight normally after birth. Further studies in these mice and in a mammary epithelial cell line revealed failure of normal STAT5 activation in the absence of ErbB3, explaining the reduction in milk-producing cells. In addition, normal activation of the enzyme Akt did not occur in ErbB3-deficient cells, leading to a failure of signaling that promotes cell survival. The findings suggest that ErbB3 plays a key role in the growth, differentiation, and survival of breast cells during pregnancy and lactation, and that it does this by promoting the activation of two pathways – the STAT5 pathway leading to growth and differentiation, and the Akt pathway that enhances cell survival. Thus, ErbB3 can be added to the signaling network that is required to prepare the mammary gland for lactation after birth of the newborn. The work is published in the journal Breast Cancer Research [M. M. Williams, et al., (2017) Breast Cancer Res., 19, 105].
Figure reproduced under the Creative Commons Attribution 4.0 International License from M. M. Williams, et al., (2017) Breast Cancer Res., 19, 105.