Provasopressin expression by breast cancer cells: implications for growth and novel treatment strategies

Abstract

SummaryThe arginine vasopressin (AVP) gene is expressed in certain cancers such as breast cancer, where it is believed to act as an autocrine growth factor. However, little is known about the regulation of the AVP protein precursor (proAVP) or AVP-mediated signaling in breast cancer and this study was undertaken to address some of the basic issues. The cultured cell lines examined (Mcf7, Skbr3, BT474, ZR75, Mcf10a) and human breast cancer tissue extract were found to express proAVP mRNA. Western analysis revealed multiple forms of proAVP protein were present in cell lysates, corresponding to those detected in human hypothalamus extracts. Monoclonal antibodies directed against different regions of proAVP bound to intact live Mcf7 and Skbr3 cells. Dexamethasone increased the amount of proAVP-associated glycopeptide (VAG) secreted by Skbr3 cells and a combination of dexamethasone, IBMX and 8br-cAMP increased cellular levels of VAG. Exogenous AVP (1, 10, and 100 nM) elevated phospho-ERK1/2 levels, and increased cell proliferation was observed in the presence of 10 nM AVP. Concurrent treatment with the V1a receptor antagonist SR49059 reduced the effects of AVP on proliferation in Mcf7 cells, and abolished it in Skbr3 cells. Results here show that proAVP components are found at the surface of Skbr3 and Mcf7 cells and are also secreted from these cells. In addition, they show that AVP promotes cancer cell growth, apparently through a Vl-type receptor-mediated pathway and subsequent ERK1/2 activation. Thus, strategies for targeting proAVP should be examined for their effectiveness in diagnosing and treating breast cancer.Keywords : arginine vasopressin (AVP) ; pro-arginine vasopressin (proAVP) ; vasopressin-associated glycopeptide (VAG) ; monoclonal antibody (mAb) ; extracellular signal-regulated kinase (ERK) ; neurophysinrelated surface antigen (NRSA)

Vasopressin V1a and V1b Receptors: From Molecules to Physiological Systems

“…Furthermore, in vitro studies have suggested a potential clinical application for V1a antagonists in treating cancer or renal disease (266,399,479).…”

“…In vitro studies have shown that the proliferative effects of AVP on cells derived from tumors are inhibited by SR49059 (relcovaptan) (266,399). Since the V1a receptor is widely expressed in various malignant cells, including neuroendocrine tumors (378) and small cell lung cancer (319), the AVP/V1a axis may represent a novel target for antitumor therapies.…”

The cocaine- and amphetamine-regulated transcript mediates ligand-independent activation of ERα, and is an independent prognostic factor in node-negative breast cancer

“…The majority of work carried out to date on this neuropeptide hormone has concentrated on its multiple neurophysiological functions (Rogge et al ., 2008). A role for neuropeptides in breast cancer is not without precedence, for example, neuropeptide Y, nerve growth factor, Oxytocin and Vasopressin have all long been associated with disease progression (Taylor et al ., 1990; Dolle et al ., 2004; Keegan et al ., 2006; Ruscica et al ., 2007; Adriaenssens et al ., 2008). …”

Native MAG-1 antibody almost destroys human breast cancer xenografts

“…Nevertheless, the effects observed are believed to result from a direct action of the antibody on the tumor cells because MAG-1 was found by us to react only with anterior hypothalamus and neurohypophysis, and not with other mouse tissues, nor with 66 normal human tissues [20]. While vasopressin and its receptors play a role in tumor breast cancer growth [7, 8, 12], the exact role of provasopressin as a surface protein remains a mystery and might not be directly connected to the mitogenic action of the hormone. Provasopressin is not a ligand for vasopressin receptors, and could itself, for these tumors, represent a receptor or scaffolding molecule for an as yet unknown ligand.…”

“…A similar tumor marker on small-cell lung cancer can be targeted in patients with antibodies [10]. A mouse IgG1 monoclonal antibody, MAG-1, directed against a C-terminal segment of provasopressin has been shown by us to give positive immunohistochemical staining with all breast cancer tissues examined, and to highlight the presence of this protein on the surface of breast cancer cells in culture [11, 12]. In this study, we examined the ability of MAG-1 and 90 Yttrium-labeled MAG-1 to arrest the growth of breast cancer xenografts in nu/nu mice.…”