Srirupa Hari Gopal and Salil K Das*
Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN, USA
Received Date: July 07, 2016; Accepted Date: July 07, 2016; Published Date: July 14, 2016
Citation: Gopal SH, Das SK (2016) Role of Lactoferrin in the Carcinogenesis of Triple-Negative Breast Cancer . J Cancer Clin Trials 1:e105.doi: 10.4172/jcct.1000e105
Copyright: © 2016 Gopal SH, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Lactoferrin is a ubiquitous, secretory, iron binding glycoprotein found in exocrine secretions such as saliva, pancreatic secretions and bile of mammals, including humans. It is considered a member of the transferrin family due to a close resemblance in molecular structure and size. Lactoferrin is produced in neutrophils and stored in specific granules. Its secretion from polymorphonuclear cells into circulation is dependent on the activation of guanylate cyclase, cGMP and protein kinase C. Lactoferrin gene expression is modulated by the steroidthyroid receptor superfamily, indicating that it is a hormone responsive gene. Lactoferrin is reported to have a variety of biological functions, including DNA synthesis, immune responses, iron transport, antimicrobial action, RNase activity, transcriptional activating functions, and receptor-mediated lipid uptake, any of which could play a role in tumor promotion [1-12]. Being a hormone responsive gene, lactoferrin may contribute to various hormone dependent cancers such as breast cancer and cancers of the female reproductive tract. In this context, it is important to note that an earlier report has shown an inverse relationship with the level of estrogen receptor and lactoferrin [13,14]. It was also found that lactoferrin and steroid hormone receptor expression are down regulated in adenocarcinomas of the endocervix, which may be associated with the loss of differentiation during neoplastic transformation . Lactoferrin expression, similar to endocervix, is highly expressed in women’s normal resting and lactating breasts, but seems to be progressively downregulated in many breast cancers.
Recently, it was also postulated that elevated levels of lactoferrin are associated with reduced expression of ERα and PR, and perhaps HER-2, and therefore could contribute to the development of triple negative breast cancer (TNBC) phenotypes . It was found that lactoferrin efficiently downregulates ERα, PR, and HER-2, and the increased invasiveness and aggression of these breast cancer cell lines was attributed to the lactoferrin-endothelin axis.
Based on the several experiments by Ha et al. , it was found that persistant exposure of breast cancer cells to lactoferrin resulted in downregulation of the hormone receptors leading to the development of TNBC phenotypes. This increase in lactoferrin was accompanied by an increase in the levels of cyclin-D which indicates cell cycle progression. It was also validated that lactoferrin uses posttranscriptional mechanisms sensitive to proteosomal degradation of proteins in order to downregulate the hormonal receptors. Tamoxifen blocked estrogen-mediated cell migration and invasiveness in ER+ cell lines. Herceptin (transtuzumab) has a similar effect on Her-2 cell lines as well. However, it was found that lactoferrin-treated cells have decreased responsiveness to both the drugs . Most importantly, it was found that lactoferrin regulates the expression of endothelin 1 (ET-1) , shown by the presence of three lactoferrin-motifs in the ET-1 promoter region. ET-1 exerts its biologic effects via an autocrine and/or paracrine manner through specific receptors, and supports tumor cell proliferation, invasion, angiogenesis and neovascularization [16-22].
A contrary study showed that treatment of human breast cancer cell lines with bovine Apo-lactoferrin increases apoptosis and decreases cell migration . But bovine lactoferrin does not bind to the endothelin 1 promoter region. Hence, ET-1 is a lactoferrin-inducible gene and only the holo form of lactoferrin is responsible for the downregulation, as well as increased invasiveness, in breast cancer cells. It was also found that the levels of lactoferrin and ET-1 were increased in TNBC specimens as compared to those in the control ER +/PR+ breast tumors .
The advent of targeted pharmacotherapy and immunotherapy for the management of different kinds of cancers has opened up new avenues for attacking cancer cells at the molecular level, thus offering the potential to manage the most aggressive tumors effectively. The use of ET-1 receptor blockers to antagonize the effects of ET-1 on tumor cells has undergone preclinical and clinical testing . Identifying the involvement of lactoferrin-endothelin axis in triple negative breast cancer opens the door to various therapeutic solutions to these aggressive and invasive cancers.
The authors acknowledge the support from Fuji Oil Company, Osaka, Japan and Meharry Translational Research Center (MeTRC) grant 5U54MD007593.
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