The mammary tissue undergoes extensive morphological and phenotypic alterations during the pregnancy/lactation cycle forming a complex network of alveolar structures (Rosen et al., 1994; Macias and Hinck, 2012). This cellular architecture exhibits well defined A/B polarization established by the adherence and tight junction protein complexes. This polarized epithelial sheet with tight junction barrier consists of mature luminal epithelial tsa hdac functionally capable of synthesis and directional secretion of milk into the lumen of the mammary gland during lactation (Anderson et al., 2007).
While our understanding of the phenotypic differentiation of the mammary epithelial cells is still limited, however, signature molecules for various stem/progenitor cell populations have been described recently (Visvader and Stingl, 2014). Adult mammary glands maintain a population of stem cells which are capable of generating epithelial progenitor cells giving rise to terminally differentiated cells. Current knowledge indicates the complex nature of the mammary stem cell (MaSC) hierarchy (Fu et al., 2014; Shehata et al., 2012). Based on the expression pattern of cell surface markers EpCAM and CD49f, a differentiation model of MaSC was proposed: EpCAMlow/CD49fhi (bipotent progenitors)-EpCAMhi/CD49fhi (luminal progenitors)-EpCAMhi/CD49flow (mature luminal cells) (Fu et al., 2014; Shehata et al., 2012). The hormonal regulations and cellular mechanisms controlling these morphogenic/phenotypic events are not fully determined.
The hormone prolactin (PRL) is known to be indispensable in regulating the development of the mammary gland and promoting the terminal differentiation of mammary epithelial cells. PRL is known to mediate these effects through activation of the Jak2/Stat5 pathway. Indeed, genetically engineered knockout mice lacking either PRL, the PRL receptor, Jak2 or Stat5 showed limited mammary alveolar development and loss of lactation capacity, implicating a potential role for PRL in mammary alveolar development (Horseman et al., 1997; Ormandy et al., 1997; Wagner et al., 2004; Liu et al., 1997). Furthermore, we have previously shown that PRL signaling through Jak2 to induce re-epithelialization of mesenchymal breast cancer cells by suppressing the process of EMT further pointing to a potential role for PRL in regulating mammary epithelial morphogenesis/polarity (Nouhi et al., 2006).
Understanding mammary gland biology is of critical significance given the prevalence of breast cancer worldwide. To characterize mechanisms involved in regulating mammary morphogenesis, extensive studies have used ex vivo culture model of mammary epithelial cells on extracellular matrices in the presence of various hormonal and growth factors. These original studies showed that mammary epithelial cells to organize into functional acinar architecture resembling mammary alveoli. Information generated using these cellular model systems have highlighted the role of the ECM component like laminin (Streuli et al., 1991, 1995) and integrin (Lee and Streuli, 2014) as important regulators of mammary acini morphogenesis. Furthermore, Xian et.al has reported the development of mammary acini using HC11 cells cultured in Matrigel in the presence of EGF (Xian et al., 2005). However, there have been no studies examining explicitly the role of PRL hormone in regulating the various aspects of acini morphogenesis. Here we describe a new role for PRL as a crucial regulator of mammary epithelial A/B polarization and luminal cell fate determination.
While there is limited information with respect to physiological ligands inducing mammary acini morphogenesis, the literature presents several growth factors, oncogenes and signaling pathways that are involved in disrupting mammary cell polarity and acini formation. Indeed, it was shown that FGF (Xian et al., 2005); TGFβ (Ozdamar et al., 2005); Erbb2 (Aranda et al., 2006) and Ephrin B1 (Lee et al., 2008) as well as NFκB (Becker-Weimann et al., 2013) to interfere with mammary acini formation/organization. Thus, our results demonstrating an organizational role for PRL in mammary acini morphogenesis is highly significant. Indeed, our results demonstrate a novel regulatory PRL-dependent mechanism coordinating mammary acini organization.