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  • The current view of mammary

    2018-10-20

    The current view of mammary acini organization and lumen formation implicate apoptosis in shaping acini lumens (Humphreys et al., 1996; Debnath et al., 2002; Mailleux et al., 2008). Indeed, studies utilizing the mammary epithelial cell line MCF10A have indicated that within the mammosphere the inner cell population undergoes anoikis due to lack of matrix attachment and growth factor exposure resulting in lumen formation and have implicated the pro-apoptotic protein Bim in this process. Our results highlight two potentially coordinated mechanisms regulating lumen formation. Indeed, while PRL treated acini show well established polarity we noticed that the lumen of these colonies are small in comparison to acini grown under HIP treatment conditions. This data implicate insulin and/or hydrocortisone in apical membrane generation/expansion. Indeed, studies performed with MDCK cytochalasin d do implicate lipid metabolism in apical membrane generation (Bryant et al., 2010). Therefore, we propose that lipid metabolism downstream of insulin is potentially leading to the expanded lumen seen in HIP treated acini. Notably, our stem cell profiling analyses using EpCAM and CD49f stem cell markers in HC11 and in primary mammary epithelial cells isolated from mid-pregnant mice showed similar profile, confirming the luminal origin of HC11 cells. Furthermore, these profiles identified only two subpopulations comprising the luminal progenitors and mature luminal cells. No basal or stromal cells could be detected (EpCAMlow/CD49fhi or EpCAMlow/CD49flow) as has been documented using primary mammary epithelial cells isolated from virgin mice. Together, these results indicate the enrichment of the luminal linage during pregnancy (Visvader and Stingl, 2014; Shehata et al., 2012). Moreover, using these cellular model systems we show that PRL through Jak2 plays a critical role as a mammary cell fate determinant inducing the differentiation of mammary progenitor cells into mature luminal cells capable of acinar morphogenesis. The role of PRL/Jak2 pathway in regulating mammary luminal maturation is also supported by the observations that Stat5a/b knockout mice show loss of mammary luminal cell population (Yamaji et al., 2009). Together our results demonstrate that PRL hormone through Jak2 kinase couples both cellular A/B polarization and mammary stem cell hierarchy. The Erk1/2 signaling cascade regulates a variety of cellular processes by phosphorylating multiple target proteins (Lefloch et al., 2009; Yoon and Seger, 2006). Our results highlighted the negative cross-talk between PRL/Jak2 and the Erk1/2 pathway to be critical in regulating both mammary epithelial A/B polarity and stem/progenitor cell differentiation. We have reported previously that this negative cross-talk was found to be important in PRL\'s ability to block EGF-induced mammary epithelial cell proliferation as well as in PRL\'s ability to block EMT process in breast cancer cells. Although the detailed network cytochalasin d of crosstalk between PRL/Jak2 and Erk1/2 pathway is yet to be established, it is likely to involve multiple mechanisms that needs to be further elaborated. Interestingly, it was reported that EpCAM expression itself may regulate cadherin mediated cell adhesion through suppression of the MAPK signaling cascade (Maghzal et al., 2013). Therefore, it is possible to postulate that PRL-mediated increase in EpCAM expression observed may ultimately lead to suppression of the Erk1/Erk2 pathway in mammary epithelial cells allowing acinar morphogenesis. Finally the results described here have important implications in expanding our understanding of the role of PRL in breast tumorigenesis. The role of PRL in breast tumorigenesis is not fully clarified. There have been reports indicating a pro-oncogenic role for PRL functioning as a local autocrine growth factor in mammary cells. Moreover, data generated from in vivo studies have highlighted PRL to play a permissive role in oncogene-induced mammary tumorigenesis (Fernandez et al., 2010; Wennbo et al., 1997; Rose-Hellekant et al., 2003). Indeed as lumen filling/repopulation of the luminal space is a hallmark of early breast tumors, we expect restoration of PRL/Jak2 signaling in breast tumor cells to induce cell polarization and promote lumen clearance. On the other hand it is known that lumen filling/repopulation of the luminal space is a hallmark of early breast tumors, therefore, we propose that restoration of PRL/Jak2 signaling in breast tumor cells to induce cell polarization and promote lumen clearance. Moreover, our findings that PRL promotes the maturation of luminal progenitor cells and induces mammary morphogenesis combined with our previous study showing PRL as a suppressor of EMT process in breast cancer cells (Nouhi et al., 2006) underscore PRL as a potential tumor suppressor and therapeutic modality against breast cancer.