Myc and Mammary Cancer: Myc is a Downstream Effector of the ErbB2 Receptor Tyrosine Kinase

The proto-oncogene c-myc encodes a transcription factor which plays a major role in the regulation of normal cellular proliferation and is aberrantly expressed in many breast tumors. In a normal cell Myc expression levels are tightly regulated being subject to many layers of control. Errantly expressed Myc collaborates with other oncogenes to promote transformation. In this review we will focus on the association between abnormal Myc expression and mammary cancer. In particular, we will discuss the role of Myc as a downstream effector of the ErbB2 receptor tyrosine kinase which is overexpressed and constitutively activate in many mammary tumors. The cooperation between Myc and ErbB2 in transformation will be discussed in relation to clinical studies on Myc in human cancer and with consideration of transgenic models of Myc-induced mammary cancer. Data from our laboratory will be presented showing that deregulated ErbB2 activity strongly stimulates cytoplasmic signaling pathways which in turn impinge on Myc at multiple levels causing its deregulated expressio

The mTOR Pathway in Breast Cancer

There is currently a wealth of information regarding the mutations that contribute to cancer development. Most of these mutations alter the expression and activity of signal transduction proteins. The current goal in cancer therapy is to use our knowledge of the molecular alterations in a cancer cell to choose the most appropriate signal transduction inhibitor for an individual patient. The topic of this review is the mammalian target of rapamycin (mTOR) kinase signaling pathway, which is aberrantly activated in many types of human cancer. We will discuss the mTOR pathway and the potential mechanisms that contribute to its activation in cancer, together with data relating to the potential for inhibitors targeting the mTOR-signaling pathway to impact on breast cancer therap

Myc and Mammary Cancer: Myc is a Downstream Effector of the ErbB2 Receptor Tyrosine Kinase

The proto-oncogene c-myc encodes a transcription factor which plays a major role in the regulation of normal cellular proliferation and is aberrantly expressed in many breast tumors. In a normal cell Myc expression levels are tightly regulated being subject to many layers of control. Errantly expressed Myc collaborates with other oncogenes to promote transformation. In this review we will focus on the association between abnormal Myc expression and mammary cancer. In particular, we will discuss the role of Myc as a downstream effector of the ErbB2 receptor tyrosine kinase which is overexpressed and constitutively activate in many mammary tumors. The cooperation between Myc and ErbB2 in transformation will be discussed in relation to clinical studies on Myc in human cancer and with consideration of transgenic models of Myc-induced mammary cancer. Data from our laboratory will be presented showing that deregulated ErbB2 activity strongly stimulates cytoplasmic signaling pathways which in turn impinge on Myc at multiple levels causing its deregulated expressio

Prolactin Mediated Intracellular Signaling in Mammary Epithelial Cells

Prolactin binds to a member of the cytokine receptor superfamily. The cytoplasmic domain of the prolactin receptor (PrlR)4 displays no enzymatic activity yet prolactin treatment leads to the induction of protein tyrosine phosphorylation. PrlR is associated with JAK2, a protein tyrosine kinase whose activity is stimulated following receptor dimerization. JAK2 subsequently phosphorylates PrlR and other cellular proteins which are recruited to the activated receptor complex. Among the JAK2 substrates is the transcription factor Stat5 whose phosphorylation mediates the transcriptional activation of β-casein gene expression. In this review we discuss the prolactin induced signaling pathways which mediate differentiation of the mammary glan

c-Myc affects mRNA translation, cell proliferation and progenitor cell function in the mammary gland

BACKGROUND: The oncoprotein c-Myc has been intensely studied in breast cancer and mouse mammary tumor models, but relatively little is known about the normal physiological role of c-Myc in the mammary gland. Here we investigated functions of c-Myc during mouse mammary gland development using a conditional knockout approach. RESULTS: Generation of c-mycfl/fl mice carrying the mammary gland-specific WAPiCre transgene resulted in c-Myc loss in alveolar epithelial cells starting in mid-pregnancy. Three major phenotypes were observed in glands of mutant mice. First, c-Myc-deficient alveolar cells had a slower proliferative response at the start of pregnancy, causing a delay but not a block of alveolar development. Second, while milk composition was comparable between wild type and mutant animals, milk production was reduced in mutant glands, leading to slower pup weight-gain. Electron microscopy and polysome fractionation revealed a general decrease in translational efficiency. Furthermore, analysis of mRNA distribution along the polysome gradient demonstrated that this effect was specific for mRNAs whose protein products are involved in milk synthesis. Moreover, quantitative reverse transcription-polymerase chain reaction analysis revealed decreased levels of ribosomal RNAs and ribosomal protein-encoding mRNAs in mutant glands. Third, using the mammary transplantation technique to functionally identify alveolar progenitor cells, we observed that the mutant epithelium has a reduced ability to repopulate the gland when transplanted into NOD/SCID recipients. CONCLUSION: We have demonstrated that c-Myc plays multiple roles in the mouse mammary gland during pregnancy and lactation. c-Myc loss delayed, but did not block proliferation and differentiation in pregnancy. During lactation, lower levels of ribosomal RNAs and proteins were present and translation was generally decreased in mutant glands. Finally, the transplantation studies suggest a role for c-Myc in progenitor cell proliferation and/or survival

Essential functions of p21-activated kinase 1 in morphogenesis and differentiation of mammary glands

Although growth factors have been shown to influence mammary gland development, the nature of downstream effectors remains elusive. In this study, we show that the expression of p21-activated kinase (Pak)1, a serine/threonine protein kinase, is activated in mammary glands during pregnancy and lactation. By targeting an ectopic expression of a kinase-dead Pak1 mutant under the control of ovine β-lactoglobulin promoter, we found that the mammary glands of female mice expressing kinase-dead Pak1 transgene revealed incomplete lobuloalveolar development and impaired functional differentiation. The expression of whey acidic protein and β-casein and the amount of activated Stat5 in the nuclei of epithelial cells in transgenic mice were drastically reduced. Further analysis of the underlying mechanisms revealed that Pak1 stimulated β-casein promoter activity in normal mouse mammary epithelial cells and also cooperated with Stat5a. Pak1 directly interacted with and phosphorylated Stat5a at Ser 779, and both COOH-terminal deletion containing Ser 779 of Stat5a and the Ser 779 to Ala mutation completely prevented the ability of Pak1 to stimulate β-casein promoter. Mammary glands expressing inactive Pak1 exhibited a reduction of Stat5a Ser 779 phosphorylation. These findings suggest that Pak1 is required for alveolar morphogenesis and lactation function, and thus, identify novel functions of Pak1 in the mammary gland development

Paneth cell - rich regions separated by a cluster of Lgr5+ cells initiate crypt fission in the intestinal stem cell niche

The crypts of the intestinal epithelium house the stem cells that ensure the continual renewal of the epithelial cells that line the intestinal tract. Crypt number increases by a process called crypt fission, the division of a single crypt into two daughter crypts. Fission drives normal tissue growth and maintenance. Correspondingly, it becomes less frequent in adulthood. Importantly, fission is reactivated to drive adenoma growth. The mechanisms governing fission are poorly understood. However, only by knowing how normal fission operates can cancer-associated changes be elucidated. We studied normal fission in tissue in three dimensions using high-resolution imaging and used intestinal organoids to identify underlying mechanisms. We discovered that both the number and relative position of Paneth cells and Lgr5+ cells are important for fission. Furthermore, the higher stiffness and increased adhesion of Paneth cells are involved in determining the site of fission. Formation of a cluster of Lgr5+ cells between at least two Paneth-cell-rich domains establishes the site for the upward invagination that initiates fission