A New Tumor Suppressor That Regulates Tissue Architecture

Pathologists use loss of normal tissue architecture as a key criterion to identify and categorize disease states. Epithelia in all glandular structures in vivo have a characteristic organization where they line a central lumen and are involved in absorptive and/or secretory functions. Under some physiological conditions—such as pregnancy, wound healing, and the periodic tissue remodeling that occurs in tissues such as colon—there is a significant increase in the rate of cell proliferation. Although the proliferation rate in these physiological conditions is higher than that seen under disease states, the overall tissue size and structure are maintained. Such maintenance of size/structure occurs because the increased proliferation is tightly coupled with tissue morphogenesis programs, resulting in remodeling of normal tissue architecture

Autocrine prolactin: an emerging market for homegrown (prolactin) despite the imports

Prolactin (PRL) is a peptide hormone that is produced by the pituitary gland and is known to regulate lactogenic differentiation. There is a significant body of evidence that points to autocrine production of prolactin and activation of an autocrine/paracrine signaling pathway to regulate cell proliferation and migration and inhibition of cell death. This perspective highlights the recent study in the October 1, 2012, issue of Genes & Development by Chen and colleagues (pp. 2154-2168) that describes a mechanism for autocrine prolactin production and places the finding in the context of a role for prolactin in breast development and cancer

A Brake Becomes an Accelerator: PTP1B-A New Therapeutic Target for Breast Cancer

The protein tyrosine phosphatase PTP1B, previously recognized for its role in downregulating insulin and leptin signaling, has now been shown to function as a positive regulator of signaling events associated with breast tumorigenesis. Inhibitors of PTP1B that have been developed as drug candidates for treatment of diabetes and obesity may offer new avenues for the treatment of breast cancer

ErbB receptors and cell polarity: New pathways and paradigms for understanding cell migration and invasion

The ErbB family of receptor tyrosine kinases is involved in initiation and progression of a number of human cancers, and receptor activation or overexpression correlates with poor patient survival. Research over the past two decades has elucidated the molecular mechanisms underlying ErbB-induced tumorigenesis, which has resulted in the development of effective targeted therapies. ErbB-induced signal transduction cascades regulate a wide variety of cell processes, including cell proliferation, apoptosis, cell polarity, migration and invasion. Within tumors, disruption of these core processes, through cooperative oncogenic lesions, results in aggressive, metastatic disease. This review will focus on the ErbB signaling networks that regulate migration and invasion and identify a potential role for cell polarity pathways during cancer progression

Shc is required for ErbB2-induced inhibition of apoptosis but is dispensable for cell proliferation and disruption of cell polarity

Amplification and overexpression of ErbB2 strongly correlates with aggressive breast cancers. A deeper understanding of pathways downstream of ErbB2 signaling that are required for the transformation of human mammary epithelial cells will identify novel strategies for therapeutic intervention in breast cancer. Using an inducible activation of ErbB2 autophosphorylation qsite mutants and the MCF-10A three-dimensional (3D) culture system, we investigated pathways used by ErbB2 to transform the epithelia. We report that ErbB2 induces cell proliferation and loss of 3D organization by redundant mechanisms, whereas it disrupts apical basal polarity and inhibits apoptosis using Tyr 1201 and Tyr 1226/7, respectively. Signals downstream of Tyr 1226/7 were also sufficient to confer paclitaxel resistance. The Tyr 1226/7 binds Shc, and the knockdown of Shc blocks the ability of ErbB2 to inhibit apoptosis and mediate paclitaxel resistance. Tyr 1226/7 is known to activate the Ras/Erk pathway; however, paclitaxel resistance did not correlate with the activation of Erk or Akt, suggesting the presence of a novel mechanism. Thus, our results show that targeting pathways used by ErbB2 to inhibit cell death is a better option than targeting cell proliferation pathways. Furthermore, we identify a novel function for Shc as a regulator of apoptosis and drug resistance in human mammary epithelial cells transformed by ErbB2. Oncogene (2010) 29, 174-187; doi:10.1038/onc.2009.312; published online 12 October 200

G-protein-coupled receptor GPR161 is overexpressed in breast cancer and is a promoter of cell proliferation and invasion

Triple-negative breast cancer (TNBC) accounts for 20% of breast cancer in women and lacks an effective targeted therapy. Therefore, finding common vulnerabilities in these tumors represents an opportunity for more effective treatment. Despite the growing appreciation of G-protein-coupled receptor (GPCR)-mediated signaling in cancer pathogenesis, very little is known about the role GPCRs play in TNBC. Using genomic information of human breast cancer, we have discovered that the orphan GPCR, G-protein-coupled receptor 161 (GPR161) is overexpressed specifically in TNBC and correlates with poor prognosis. Knockdown of GPR161 impairs proliferation of human basal breast cancer cell lines. Overexpression of GPR161 in human mammary epithelial cells increases cell proliferation, migration, intracellular accumulation of E-cadherin, and formation of multiacinar structures in 3D culture. GPR161 forms a signaling complex with the scaffold proteins beta-arrestin 2 and Ile Gln motif containing GTPase Activating Protein 1, a regulator of mammalian target of rapamycin complex 1 and E-cadherin. Consistently, GPR161 amplified breast tumors and cells overexpressing GPR161 activate mammalian target of rapamycin signaling and decrease Ile Gln motif containing GTPase Activating Protein 1 phosphorylation. Thus, we identify the orphan GPCR, GPR161, as an important regulator and a potential drug target for TNBC

A novel role for 14-3-3σ in regulating epithelial cell polarity

The loss of epithelial polarity is thought to play an important role during mammary tumor progression. Using a unique transgenic mouse model of ErbB2-induced mammary tumorigenesis, we demonstrated previously that amplification of ErbB2 is frequently accompanied by loss of the 14-3-3σ gene. Here, we demonstrate that ectopic expression of 14-3-3σ results in restoration of epithelial polarity in ErbB2-transformed mammary tumor cells. We further demonstrate that targeted deletion of 14-3-3σ within primary mammary epithelial cells increases their proliferative capacity and adversely affects their ability to form polarized structures. Finally, we show that 14-3-3σ can specifically form complexes with Par3, a protein that is essential for the maintenance of a polarized epithelial state. Taken together, these observations suggest that 14-3-3σ plays a critical role in retaining epithelial polarity. © 2010 by Cold Spring Harbor Laboratory Press