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Articles

Polyunsaturated Fatty Acids and Epidermal Growth Factor Receptor/Mitogen-Activated Protein Kinase Signaling in Mammary Cancer¹

Department of Large Animal Clinical Sciences, Virginia–Maryland Regional College of Veterinary Medicine–Virginia Tech, Blacksburg, Virginia 24061-0442

²To whom correspondence should be addressed at Department of LACS, Virginia–Maryland Regional College of Veterinary Medicine–Virginia Tech, Phase II–Duckpond Drive, Blacksburg, VA 24061-0442. E-mail: kesaker{at}vt.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PUFA and Mammary Cancer. Epidemiological Studies. Cell Line and Rodent... Epidermal Growth Factor Receptor... PUFA and EGFR/Mitogen-Activated... Summary and Perspectives. REFERENCES

 
Mammary cancer is the second leading cause of cancer death in women, the second most common neoplasm in dogs and the third leading neoplasm in cats. Mammary tumors are similar in morphology and progression in these species, so cats and dogs are good models for determining treatment or prevention modalities for the human population. Epidemiological, in vitro and rodent studies have demonstrated that polyunsaturated fatty acids (PUFA) can influence the growth, progression and metastasis of mammary cancer. Although a role of PUFA in modulating mammary cancer growth has been shown, the mechanisms by which this occurs remain unclear. Recent studies have demonstrated that PUFA may influence the activity of the epidermal growth factor receptor/mitogen-activated protein kinase pathway, which is involved in regulating several oncogenes (c-myc, c-fos, neu/c-erb-b2) involved in the progression of cancer. We review the potential mechanism by which PUFA may modulate the growth of mammary cancer through regulation of the epidermal growth factor receptor/mitogen-activated protein kinase signal transduction cascade.

KEY WORDS: • mammary cancer • polyunsaturated fatty acids • mitogen-activated protein-kinase • epidermal growth factor receptor

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PUFA and Mammary Cancer. Epidemiological Studies. Cell Line and Rodent... Epidermal Growth Factor Receptor... PUFA and EGFR/Mitogen-Activated... Summary and Perspectives. REFERENCES

 
Mammary gland neoplasms are common in both human and companion animal populations. Mammary cancer is the second leading cause of cancer death in women, and mammary gland tumors are the second most common type of neoplasm in both male and female dogs (surpassed only by skin tumors) (1) and the third most common neoplasm in cats (2) .

The cat is a good model for human mammary growth and tumorigenesis due to similarities in morphology, histopathology and patterns of malignancy (3) . Therefore, determination of treatment or prevention modalities for the feline population not only is beneficial to the pet population but also may prove useful to humans. Many factors, including hormonal stimulation and nutrients, may play a role in the development of this disease in both humans and pets.

Several nutrients, such as vitamins E (4) , D (5) and B-6 (6) , have been reported to alter the growth of human mammary cancer cells in vitro. Clearly, nutrients may be important modulators of human mammary cancer cell growth, and further study of mechanisms involved may identify new targets against mammary cancer cell growth and could have a significant impact on the treatment and/or prevention of this disease. A class of nutrients that may have a promising role in the prevention and/or treatment of mammary cancer is the polyunsaturated fatty acids (PUFA).³ In this review, we consider the research relating PUFA to mammary cancer progression and prevention and attempt to present some possible mechanisms by which PUFA exert their effects in mammary tissue.

	PUFA and Mammary Cancer.

TOP ABSTRACT INTRODUCTION PUFA and Mammary Cancer. Epidemiological Studies. Cell Line and Rodent... Epidermal Growth Factor Receptor... PUFA and EGFR/Mitogen-Activated... Summary and Perspectives. REFERENCES

 
Linoleic acid [(n-6), LA] is the principal PUFA in the U.S. diet (7) [although there are several fish sources of (n-3) PUFA [linolenic (LNA), eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids] widely available in the United States] (8) . In the body, LA is converted to arachidonic acid (AA), and LNA is converted to EPA and then subsequently to DHA by a variety of desaturase isoforms. The (n-3) and (n-6) fatty acids compete for desaturase enzymes, so an increased consumption of LNA, EPA and DHA can decrease the production of AA by being preferentially metabolized by those enzymes (9) .

One of the main functions of PUFA in the body is as a precursor for eicosanoids, mediators of inflammation and cellular growth. PUFA are converted to prostaglandins by cyclooxygenases and to leukotrienes by lipoxygenases (LOX). AA and EPA compete for cyclooxygenases and LOX, resulting in the production of eicosanoids with opposing effects. In general, AA-derived eicosanoids, such as 2-series prostanoids and 4-series leukotrienes, have proinflammatory effects, whereas EPA-derived eicosanoids, such as 3-series prostanoids and 5-series leukotrienes, have anti-inflammatory effects. There is competition and opposition of PUFA in the body, so research has been conducted to determine the importance of the (n-3)-to-(n-6) PUFA ratio, rather than the absolute level of either class of PUFA, in cancer progression.

	Epidemiological Studies.

TOP ABSTRACT INTRODUCTION PUFA and Mammary Cancer. Epidemiological Studies. Cell Line and Rodent... Epidermal Growth Factor Receptor... PUFA and EGFR/Mitogen-Activated... Summary and Perspectives. REFERENCES

 
Epidemiological studies in humans during the past two decades have demonstrated that the consumption of fish oil has a protective effect against the development of mammary cancer (10) . Fish oil contains mostly (n-3) PUFA, whereas vegetable oils (the major fatty acid contributor in the Western diet) contain (n-6) PUFA; therefore, it has been hypothesized that (n-3) and (n-6) PUFA have different effects on the growth and progression of mammary tumors. Epidemiological evidence supports this hypothesis. Female breast cancer mortality rates in Japanese women have steadily increased during the past 40 y (11) . Increased breast cancer rates in the Japanese population have been accompanied by increased use of LA-rich vegetable oils and decreased consumption of fish, resulting in a decreased dietary (n-3)-to-(n-6) PUFA ratio (12) . Lanier and coworkers (13 ,14) showed that breast cancer rates (annual age-adjusted per 100,000 individuals) in the Alaskan Eskimo population increased from 0.9 to 86.5 during a 20-y period and that, again, the increased cancer incidence was accompanied by the westernization of this population’s culture and dietary habits. Westernization of these cultures has changed lifestyle factors other than diet that may play a role in the increased breast cancer rates, but evidence does suggest that diet, specifically a high (n-3)-to-(n-6) PUFA ratio, may have a protective effect on mammary cancer incidence in humans.

Klein et al. (15) reported that low -LNA levels in mammary adipose tissue was inversely correlated to increased mammary cancer risk in women. These correlational studies strongly suggest that the ratio of (n-3) to (n-6) PUFA in vivo may in fact play a protective role against the development of mammary tumors and that (n-3) and (n-6) PUFA have different effects on the development and progression of these tumors.

	Cell Line and Rodent Studies.

TOP ABSTRACT INTRODUCTION PUFA and Mammary Cancer. Epidemiological Studies. Cell Line and Rodent... Epidermal Growth Factor Receptor... PUFA and EGFR/Mitogen-Activated... Summary and Perspectives. REFERENCES

 
It has been shown that (n-3) PUFA, specifically EPA and DHA, have inhibitory effects and that (n-6) PUFA (LA) have stimulatory effects on mammary cancer cell line growth in vitro (16 ,17) . A tumor-promoting effect for (n-6) PUFA was shown in rats treated with chemical carcinogens, whereas (n-3) PUFA were shown to have an inhibitory effect on tumor growth in these same rats (18) . More specifically, an EPA- or a DHA-supplemented diet with a final (n-3)-to-(n-6) ratio of 1:1.8 significantly decreased the incidence of mammary tumors in rats challenged with chemical carcinogens (19) . Furthermore, it has been demonstrated that dietary (n-3) PUFA supplementation (EPA, DHA) can suppress growth and metastasis of xenograft mammary tumors in athymic nude mice compared with unsupplemented controls (20 ,21) . Supplementation with (n-3) PUFA has also been shown to inhibit local recurrence and metastases of mammary tumors in xenograft-bearing mice whose primary tumors had been excised (22) . These studies appear to support epidemiological evidence concerning the protective role that a high (n-3)-to-(n-6) PUFA ratio may have against the development of mammary cancer and to provide evidence that (n-3) PUFA could have the potential to be used as an adjuvant therapy to prevent recurrence and metastases of mammary cancer. Subsequent sections of this review present evidence concerning possible mechanisms of PUFA in cancer cells.

	Epidermal Growth Factor Receptor and Mammary Cancer.

TOP ABSTRACT INTRODUCTION PUFA and Mammary Cancer. Epidemiological Studies. Cell Line and Rodent... Epidermal Growth Factor Receptor... PUFA and EGFR/Mitogen-Activated... Summary and Perspectives. REFERENCES

 
Signaling mechanisms that result in cell proliferation are closely associated with tumor growth and progression. Epidermal growth factor receptor (EGFR) is a membrane-bound protein involved in the signal transduction and subsequent growth stimulation of cells. Enhanced expression of EGFR has been shown to play a role in the growth of both normal and neoplastic mammary tissue. Rutteman et al. (23) demonstrated that in canine mammary tissue, a significant relationship existed between the concentrations of EGFR in benign and metastatic lesions and the proportion of tumor to stroma cells in that tissue. In humans, it has been demonstrated that increased expression of EGFR is directly related to invasiveness of mammary tumors (24) , that EGF promotes tumorigenesis in mouse models (25) , that overexpression of EGFR leads to hormone unresponsiveness in tumors that express high levels of estrogen receptor (25) and that EGF can modulate the expression of neu (c- erb-b2) proto-oncogene in human mammary cancer cell lines in vitro (26) . HER2/neu, a surface membrane protein with similar structure and function to EGFR, is overexpressed in 25% of human mammary cancers (27) . The neu myc, fos, jum gene product is also found in feline mammary tissue, suggesting that similar mechanisms of mammary cancer regulation by EGFR may be observed in both humans and felines (3) . Overexpression of HER2/neu in human breast cancer results in ligand-independent activation of mitogenic signal transduction and increased cell proliferation (27) . Trastuzumab (Herceptin; Genentech, San Francisco, CA), an anti-HER2 antibody, has clinical activity in patients with breast cancers that overexpress HER2 (28) , and it has been hypothesized that the action of trastuzumab is exerted through the modulation of signal transduction in those patients (27) . It is conceivable that nutrients or other therapeutic agents that act to modulate these signal transduction pathways may prove useful for the regulation of cancer growth and metastasis.

	PUFA and EGFR/Mitogen-Activated Protein Kinase.

TOP ABSTRACT INTRODUCTION PUFA and Mammary Cancer. Epidemiological Studies. Cell Line and Rodent... Epidermal Growth Factor Receptor... PUFA and EGFR/Mitogen-Activated... Summary and Perspectives. REFERENCES

 
Studies show that dietary PUFA may regulate the growth and progression of mammary cancer through the modulation of EGFR. The current view of the EGFR pathway is as follows: EGF binds to trans-membrane EGFR-tyrosine kinase, and ligand-bound EGFR dimerize, which activates a signal transduction cascade, thus inducing the activity of a variety of kinases, including a GTP-bound Ras, Raf-1, MAPK kinase (MEK) and mitogen-activated protein kinase (MAPK) (Fig. 1 ). MAPK constitutes a family of serine/threonine kinases that are regulated by a number of growth factors and oncogenes. MAPK may be the link that connects signal transduction of EGFR to transcriptional activation in the nucleus.

View larger version (24K): [in this window] [in a new window]   Figure 1. Epidermal growth factor receptor/mitogen-activated protein kinase (EGFR/MAPK) signaling cascade. Recruitment of signaling molecules to activated EGFR initiates a series of successive phosphorylations and activation of kinases in the MAPK family (Raf-1, MEK, MAPK), which in turn mediate transcription factors (i.e., myc, fos, jun) regulating cell growth and mitogenesis. Parts of this figure were adapted with permission from Seger (44) .

The activation of Ras, another upstream effector of MAPK, has been shown to up-regulate bcl-2, a suppressor of apoptosis (30) , suggesting that MAPK may play a role in the progression of mammary cancer through both growth stimulation and decreased apoptosis. It has been demonstrated that the inhibition of MAPK can lead to inhibition of mammary cancer cell growth and enhanced killing of mammary cancer cells by cytotoxic compounds. Inhibition of MAPK in MCF-7 human mammary cancer cells resulted in inhibition of estrogen-induced growth in these cells (31) . Fiddes et al. (32) demonstrated that MAPK inhibitors could inhibit cell-cycle progression in mammary carcinoma cells. Inhibition of MAPK has also been shown to increase the induction of apoptosis in tumor cells (33) , implying that MAPK may not only stimulate the growth of mammary cancer cells but also prevent cancer cell death through apoptosis.

There is evidence that the mammary fat pad may modulate the growth of mammary epithelial cells by regulating EGFR. Hovey et al. (34) demonstrated that EGF-stimulated growth of mammary epithelial cells was significantly increased by incubation with mammary fat pad. Dietary PUFA intake has been shown to directly affect the composition of PUFA in feline adipose tissue (35) . It is conceivable that changes in PUFA consumption could influence growth in mammary tumors by altering the PUFA composition of the surrounding fat pad. There are several proposed mechanisms by which PUFA might regulate the EGFR/MAPK–induced growth of mammary cancer cells (Fig. 2 ). Researchers have demonstrated that AA can inhibit GTPase-activating proteins (36) , which are involved in the hydrolysis of GTP-bound (active) Ras protein in the EGFR/MAPK cascade. By inhibiting the GTPase-activating protein, AA prolongs the signal transduction of EGFR to the nucleus, leading to increased growth stimulus. (n-6) PUFA and their lipoxygenase metabolites have been implicated in the activation of several isoforms of protein kinase C (PKC) (37 ,38) , which are effectors of MAPK signaling. In vivo, PKC- and PKC- have been shown to activate Raf-1, and PKC-ß has been shown to activate Mek and subsequently MAPK (39) . This provides evidence that (n-6) PUFA may influence the MAPK mitogenesis of cells through a variety of mechanisms. Raf-1 must be recruited to the cell membrane to interact with GTP-bound Ras. The recruitment of Raf-1 is mediated through direct interaction with membrane fatty acids (40) , and the localization of Ras to the membrane requires the addition of a lipid group (farnesyl). It has been shown that without this lipid group, and subsequent membrane localization, Ras cannot interact with the necessary molecules to initiate the MAPK signaling cascade (41) .

View larger version (28K): [in this window] [in a new window]   Figure 2. (n-6) Polyunsaturated fatty acid (PUFA) stimulation of the epidermal growth factor receptor/mitogen-activated protein kinase (EGFR/MAPK) cascade. A, Inactivation of GTPase activating protein by (n-6) PUFA leads to retained mitogenic and proliferation activities of MAPK. B, (n-6) PUFA stimulates protein kinase C (PKC), which in turn activates several components of the MAPK signaling cascade. Parts of this figure were adapted with permission from Seger (44) .

	Summary and Perspectives.

TOP ABSTRACT INTRODUCTION PUFA and Mammary Cancer. Epidemiological Studies. Cell Line and Rodent... Epidermal Growth Factor Receptor... PUFA and EGFR/Mitogen-Activated... Summary and Perspectives. REFERENCES

 
Since 1987, when the first association was made between EGFR/MAPK and mammary cancer, many drugs that target this pathway have been in development. These drugs include monoclonal antibodies against different domains of the EGFR or HER2/neu receptor, kinase inhibitors to prevent the phosphorylation of EGFR or other components of the signal transduction cascade (Raf, MEK, MAPK) and compounds to block the lipid-mediated component of the EGFR/MAPK pathway (farnesylation inhibitors). Recent data have demonstrated the effectiveness of (n-3) PUFA in regulating growth, progression, metastasis and postexcision recurrence of mammary tumors in murine models. Furthermore, studies presented in this review provide evidence that PUFA can influence EGFR/MAPK, targeting many of the same components as drugs under development. Clearly, these data suggest that further research into the usefulness of dietary manipulation of PUFA for the prevention and/or adjuvant treatment of mammary cancer, as well as continued research into the mechanisms of PUFA in mammary tumor development, is needed.

The data suggest that the most important aspect of PUFA in the prevention of mammary cancer is the ratio of (n-3) to (n-6) PUFA rather than the absolute concentration of either. Research indicates that a ratio of 1:1–1:2 has the most protective effect against the development and growth of mammary cancers. If this is indeed the case, a closer look at human and animal diets, whose (n-3)-to-(n-6) average ratio is considerably higher (1:20 and 1:10, respectively) (8 ,43) , may be warranted. With mammary cancer prevalent in the pet population, several areas of research could be addressed. Based on statistics, mammary cancer is a growing problem in the feline pet population and tends to be malignant and associated with a high incidence of complications (1) . Future studies should focus on elucidating mechanisms by which PUFA regulate cancer growth and progression in cats, as well as dogs and humans. Results from those studies may provide information to produce novel treatment and prevention options for both the human and pet populations, as well as information useful in guiding the formulation of diets to enhance the protection and/or the recovery/convalescence of pets and humans being treated for cancer. Finally, data generated in future studies could provide information concerning the use of (n-3) PUFA as a novel chemopreventative or adjuvant therapeutic agent for both human and animal patients with mammary cancer.

	FOOTNOTES

 
¹ Manuscript received 7 December 2000.

³ Abbreviations used: AA, arachidonic acid; DHA, docosahexanoic acid; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; EPA, eicosapentanoic acid; LA, linoleic acid; LNA, linolenic acid; LOX, lipoxygenases; MAPK, mitogen-activated protein kinase; PKC, protein kinase C; PUFA, polyunsaturated fatty acids.

	REFERENCES

TOP ABSTRACT INTRODUCTION PUFA and Mammary Cancer. Epidemiological Studies. Cell Line and Rodent... Epidermal Growth Factor Receptor... PUFA and EGFR/Mitogen-Activated... Summary and Perspectives. REFERENCES

 

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