Research ArticleResearch Article

The Role of Inflammation in Breast Cancer and Prostate Cancer

Wen-liang ZHANG
Clinical Oncology and Cancer Research June 2011, 8 (2) 77-84; DOI: https://doi.org/10.1007/s11805-011-0563-y

Abstract

Inflammatory conditions increase the risk of cancer. Strong evidences showed that inflammation contributes to breast cancer and prostate cancer in different ways such as inflammation-induced DNA or RNA damage, overexpression cytokines, chemokines etc. Recent studies have begun to unravel molecular pathways linking inflammation and cancer. Some possible mechanisms by which inflammation can contribute to carcinogenesis have been found. These mechanisms by which inflammation contributes to cancer give broader views of cancer development. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.

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Introduction

Cancer and inflammation, both play important roles in human life. Cancer is a leading cause of death worldwide and accounted for 7.6 million deaths (around 13% of all deaths) in 2008, and currently, 1 in 4 deaths in the United States is due to cancer[1]. Inflammation, especially chronic inflammation, which can cause heart disease, diabetes, cancer, stroke, and alzheimer’s is another leading factor in most of the disease-based causes of death[2–5]. The functional relationship between cancer and inflammation was proposed by Rudolf Virchow, who noticed the infiltration of leukocytes in malignant tissues, more than a century ago[2].

In recent years, more and more data from experimental, clinical and epidemiological studies support that inflammation and cancer are linked. A number of cancers such as colorectal cancer, hepatocellular carcinoma, mesothelioma, bronchial lung cancer, and bladder cancer et al. have been linked to inflammatory origins[6]. Approximately, 25% of all cancers are somehow associated with chronic infection and inflammation[7].

We know that both prostate and breast are very important to men and women respectively. Prostate cancer is one of the 3 major cancers in men and breast cancer is also one of the major cancers in women. So the relationships between prostate cancer, breast cancer and inflammation will be the focuses of this review[1].

Inflammation is a defense mechanism the body uses to protect itself against infection and injury. Chronic inflammation arises when the immune system doesn’t shut off. It continues its healing response and the inflammatory cascade of events can occur for weeks, months or even years. Then inflammation not only destroys germs, but can also destroy organs. Chronic inflammation is associated with arthritis, diabetes, Alzheimer’s, heart disease, multiple sclerosis, cancer and prostate conditions[8, 9].

Nuclear factor-κB

NF-κB is a protein complex that controls the transcription of DNA. It is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized low density lipoprotein (LDL), and bacterial or viral antigens[10–12]. However, incorrect regulation of NF-κB has been linked to cancer, inflammation other diseases (Fig.1).

Fig. 1.
Fig. 1.

Overview of how inflammation contributes to cancer.

Activation of the transcription factor NF-κBis the central to the inflammatory responses. Bacterial lipopolysaccharides, viral transactivating proteins, double-stranded RNA, cytokines and reactive oxygen species can activate NF-κB. Activated NF-κB can induce the expression of many pro-inflammatory cytokines, adhesion molecules, chemokines, growth factors and other mediators of inflammation such as cyclooxygenase-2 (COX-2)[13], nitric oxide (NO) synthase and angiogenic factors. In addition, NF-κB is an activator of antiapoptotic genes[14], by inducing antiapoptotic genes (e.g. Bcl2), it promotes survival in tumor cells and in epithelial cells targeted by carcinogens, providing a mechanism whereby chronic inflammation may confer survival benefits to cancer cells. A number of studies provided unequivocal evidence that NF-κB is involved in tumor initiation and progression in tissues in which cancer-related inflammation (CRI) typically occurs (such as the gastrointestinal tract and the liver)[15–17]. In addition to effects on cell survival, and the production of growth and angiogenesis factors, NF-κB might directly stimulate cell-cycle progression through transcriptional activation of cell-cycle genes, especially cyclin D1[18].

Inflammation and the development of prostate cancer

The prostate is a walnut-sized glandular structure located at the base of the bladder and wrapped around the urethra. Its main role is the production of fluid which provides nutritional support to semen[19].

Prostate cancer is the most common non-cutaneous malignant neoplasm in men in Western countries, responsible for the deaths of approximately 30,000 men per year in the United States[20]. African-American men have the highest incidence and mortality rates from prostate cancer (National Cancer Institute). Men in South East Asian countries have a comparatively low incidence of prostate cancer, for example, there is a nearly 30- and 10-fold difference in the incidence and mortality rates, respectively, from prostate cancer between African-American and Hong Kong and Japan populations[19]. But incidence of prostate cancer increases rapidly after South East Asian men immigrated to the West, so the pathogenesis of prostate cancer is not an intrinsic feature of ageing. Both genetics and environmental factors may contribute to prostate cancer[21].

There is emerging evidence that prostate inflammation and inflammatory atrophy of the prostate contribute to the development of carcinomas prostate[8, 9]. Daniels et al. found positive associations for a self-reported history of prostatitis with a history of prostate cancer in the ‘osteoporotic fracture in men’ study, a cross-sectional analysis from a prospective cohort study of 5821 men. They found that men with a history of prostatitis were more likely to self-report a history of prostate cancer (26% vs. 7%; P < 0.0001) and a history of benign prostatic hyperplasia (83% vs. 38%; P < 0.0001) within a lifetime compared with men without a history of prostatitis[22].

Prostate inflammation

Prostate Inflammatory processes can be caused by chemical, physical or biological agents. And a variety of potential sources account for the initiation of prostatic inflammation, including direct infection, dietary factors, oestrogens, or a combination of two or more of these factors[21].

Diet

Saturated fats from such foods as beef, pork and butter increase the body’s inflammation levels and contribute to prostate cancer. Omega-6 fatty acids increased prostate tumor growth, and has sped up histopathological progression, and decreased survival[23]. Too much intake of dairy and excess consumption of simple sugars could contribute to negative health conditions associated with prostate inflammation and an elevated risk of prostate cancer[24,25]. Folic acid supplements have recently been linked to an increase in risk of developing prostate cancer[26]. A small Swedish study of 254 subjects showed that folate could result in a 3 fold increase in early prostate cancer development and risk[27].

Microbial infection

Lots of pathogenic organisms have been found to induce prostate inflammation and contribute to prostate cancer. These include E. coli, Klebsiella, Enterobacter and Proteus[28,29]. A report in Journal of the National Cancer Institute showed that Trichomonas vaginalis (T. vaginalis) seropositivity was associated with a significant twofold increased risk of advanced prostate cancer, and an almost three-fold increased risk of prostate cancer that progresses to bone metastases and death[30]. Infection with chlamydia, gonorrhea, or syphilis seems to increase the chance for prostate cancer[31]. And Schlaberg et al. found that a newly found a gammaretrovirus, xenotropic murine leukemia virus-related virus (XMRV) was associated with prostate cancer especially high-grade tomors[32].

Hormone

Oestrogens (estrogens), are a group of compounds named for their importance in the estrous cycle of humans and other animals, and functioning as the primary female sex hormones. In males, oestrogen regulates certain functions of the reproductive system important to the maturation of sperm[33–35]. Stuart et al. showed that increased endogenous estrogen synthesis leads to the sequential induction of prostatic inflammation (prostatitis) and prostatic pre-malignancy[36]. And also Wang et al. showed that oestrogen played a pivotal role in prostate inflammation and malignancy[37].

Proliferative inflammatory atrophy (PIA)

In the prostate, epithelial tissue damage followed by cell regeneration in the presence of inflammation is believed to be a key event in neoplastic transformation. According to the ‘injury and regeneration’ model, inflammatory cells infiltrating the prostate release reactive species in response to bacterial/viral infection, uric acid, or dietary prostate carcinogens. Besides inducing inflammation, tissue injury by these and other agents would promote the appearance of proliferative inflammatory atrophy (PIA), which represents a precursor lesion to prostatic intraepithelial neoplasia and, therefore, prostatic carcinoma[38, 39].

Prostate carcinogenesis

Oxidative stress

When infection happens, one of the mechanisms by which cells fight infection is by the production of reactive oxygen and nitrogen species. Reactive molecules, such as H202 and nitric oxide (NO), are released from the inflammatory cells and can interact with DNA in the proliferating epithelium to produce permanent genomic alterations such as point mutations, deletions, and rearrangements[40–44]. DNA damage caused by reactive oxygen and nitrogen species can cause mutation, which is an important factor in tumor initiation[45].

Erythroid 2p45 (NF-E2)-related factor 2 (Nrf2) is a basic-region leucine zipper transcription factor that mediates the expression of key protective enzymes through the antioxidant-response element (ARE). Frohlich et al showed that Nrf2 was extensively decreased in human prostate cancer and the decrease of Nrf2 leads to increased oxidative stress and ultimately DNA damage associated with tumorigenesis in the prostate gland[46].

Barnett et al showed that Snail transcription factor, an inducer of epithelial-mesenchymal transition (EMT) could increase concentration of reactive oxygen species (ROS), specifically, superoxide and hydrogen peroxide, and then increase ROS-mediated EMT and contribute to prostate tumor progression[47].

NF-kB activation

The NF-KB family of transcription factors has been shown to be constitutively activated in various human malignancies, including prostate cancer. Constitutive NF-KB activity has also been demonstrated in primary prostate cancer tissue samples. NF-KB may promote cell growth and proliferation in prostate cancer cells by regulating expression of genes such as c-myc, cyclin D1, and IL-6. NF-KB may also inhibit apoptosis in prostate cancer cells through activation of expression of antiapoptotic genes, such as Bcl-2. Also NF-KB-mediated expression of genes involved in angiogenesis (IL-8, VEGF), and invasion and metastasis (MMP9, uPA, uPA receptor) may further contribute to the progression of prostate cancer[48–50].

IL-6 has been suggested to function as a possible paracrine or autocrine growth factor for human prostate carcinoma cells[51]. Indeed, NF-kB activity was shown to be essential for constitutive expression of IL-6 in androgen-independent prostate cancer cells[52].

ERK and p38 MAPK activation

The ERK, p38 MAPK are activated by stress signals such as inflammtory cytokines, heat shock, ultraviolet light, etc[53]. Mounting evidence suggests that the p38 MAPK signaling cascade is involved in various biological responses other than inflammation such as cell proliferation, differentiation, apoptosis and invasion[54]. Uzgare et al showed that Erk1/2, and p38MAPKs were activated during prostate cancer initiation and progression[55].

The p38 MAPK pathway has been shown to regulate the expression of the MMP family[56–58], and it has been demonstrated that prostate cancer cell invasion is mediated through the p38 MAPK pathway; this leads to the phosphorylation of heat shock protein 27, which in turn regulates MMP-2 activation and cell invasion[59].

Inflammation and the development of breast cancer

The female breast is made up mainly of lobules (milk-producing glands), ducts (tiny tubes that carry the milk from the lobules to the nipple), and stroma (fatty tissue and connective tissue surrounding the ducts and lobules, blood vessels, and lymphatic vessels).

Breast cancer is a malignant tumor that starts from cells of the breast. Most breast cancers begin in the cells that line the ducts (ductal cancers). Some begin in the cells that line the lobules (lobular cancers), while a small number start in other tissues.

Breast cancer is the most common cancer among American women, except for skin cancers. The chance of developing invasive breast cancer at some time in a woman’s life is a little less than 1 in 8 (12%). White women are slightly more likely to develop breast cancer than are African-American women. Breast cancer is the second leading cause of cancer death in women, exceeded only by lung cancer. The chance that breast cancer will be responsible for a woman’s death is about 1 in 35 (about 3%). African-American women are more likely to die of this cancer[60].

Breast inflammation

In the breast microenvironment, cellular proteins, lipids, and DNA are at risk of chemical derangements, damage, or mutation when exposed to disruptive factors emanating from sources endogenous and/or exogenous to the human body such as alcohol, obesity, radiation and so on. In response to such factors, oxidative stress ensues[61]. It is well-known that oxidative stress leads to DNA damage, malfunctioning mitochondria, cell membrane damage, and cell death. These aberrations within the cell are proinflammatory, and the result is the initiation of the inflammatory response[62].

Breast carcinogenesis

Oxidative stress

Reactive oxygen species (ROS) also plays a role of ROS in breast carcinoma. Markers of constitutive oxidative stress such as hydrogen peroxide etc. have been detected in samples from in vivo breast carcinomas[63]. And increased steady-state levels of DNA base damage, with a pattern characteristic of hydroxyl radical (.OH) attack, have been reported in DNA from invasive ductal carcinoma[64, 65].

8-Hydroxy-2’-deoxyguanosine, one of the major oxidatively modified DNA base products, is almost 10 times more prevalent in invasive ductal breast carcinoma cells than in normal control samples from the same patient[63]. Oxidative stress within breast tumours may also facilitate invasion and metastasis by activating MMPs and inhibiting antiproteases. MMP-2 is a gelatinase that is believed to play a major role in breast cancer invasion and metastasis. High levels of MMP-2 correlate with poor prognosis in breast cancer patients and ROS have been shown to activate MMP-2, possibly by the reaction of oxygen radicals with thiol groups within MMP-2[66–68].

Oxidative stress also can activate of growth-promoting signalling pathways such as, for example, hyperphosphorylation of c-Jun by oxidative stress activates activator protein-1 in MCF-7 breast carcinoma cells, a response that stimulates proliferation[69].

NF-κB activation

There is emerging evidence that NF-kB also plays a vital role in breast cancer (Fig.1). NF-kB family members are overexpressed or aberrantly activated in breast cancer cell lines, primary human breast tumors and in rat mammary tumors from the aromatic hydrocarbon-induced model of breast cancer[70, 71]. Sovak et al showed that direct inhibition of NF-kB activity in breast cancer cells could induce apoptosis[71].

Wu et al showed that TNFa induced NF-kB activation could induce protein stabilisation of Snail and β-catenin by inhibiting GSK-3β-mediated phosphorylation, which contributes to EMT induction and invasion in breast tumor cells[72]. Hung group[73] found that NF-kB activation could resulting in suppression of tuberous sclerosis 1 (TSC1), which forms a complex with tuberous sclerosis 2 (TSC2) and serves as a repressor of the mammalian target of rapamycin (mTOR)pathway, which regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription[74, 75], and disruption of TSC1/TSC2 complex function could activate mTOR pathway, and results in breast cancer development. Activation of NF-kB also could induce vascular endothelial growth factor (VEGF), which enhances angiogenesis and contributes to breast cancer progression[73].

p38 MAPK activation

A study indicated that the p38 MAPK pathway might enhance breast cancer progression by upregulating uPA expression, and might be an important route in invasion and metastasis of breast cancer[76]. Shin et al showed that H-Ras-specific activation of the Rac/MKK-6/p38 MAPK signaling pathway upregulated MMP-2, leading to invasion and migration of MCF10A cells[58]. It is believed that the uPA/uPA receptor/plasminogen network activates pro-MMP-1, -MMP-3, -MMP-9, and - MMP-13 produced by stromal cells. Activated MMPs break down the physical barriers of metastasis, thus promoting invasion, intravasation, and extravasation of cancer cells including breast cancer cells[77–79]. Phosphorylation of heat shock protein 27 by p38 MAPK has been shown to induce the migration of MDA-MB-231 breast cancer cells on a laminin-5-coated dish[80]. It was also suggested that p38 MAPK might be critical in heregulin-b1-mediated MMP-9 induction in breast cancer cells[81].

Chemokine pathway

Chemokine receptors and their ligands are key orchestrators of leukocytes trafficking in homeostatic conditions as well as during inflammation and cancer. Further evidence has highlighted that chemokine and their receptors are part of the molecular pathways that drive cancer cell motility, invasiveness and survival[82]. For example, the chemokines receptor C-X-C chemokine receptor type 4 (CXCR4) is frequently upregulated by malignant cells and for different types of tumors including breast cancer, and its expression levels by primary tumors correlates with the frequency of lymphonodes metastasis[83]. Helbig et al showed that NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4[84].

Other pathway

Clinical and experimental data suggest that chronic inflammation also can promote mammary tumor development through mechanisms involving chronic activation of humoral immunity and infiltration of Th2 cells and polarized innate inflammatory cells[85].

C-reactive protein (CRP) is a protein found in the blood, the levels of which rise in response to inflammation. Breast cancer patients have elevated concentrations of C-reactive protein (CRP) before surgery, more so in women with advanced cancer, suggesting that CRP may be related to tumor burden or progression[86, 87].

Treatment

Given the importance of chronic inflammation to carcinogenesis, it’s important to prevent or alleviate inflammation during cancer therapy. There are a variety of ways we can prevent or alleviate inflammation:

Lifestyle changes

According to the Linus Pauling Institute at University of Oregon, avoiding animal products, refined sugar, refined vegetable oils, and refined carbohydrates can help you to prevent inflammation. Anti-oxidant rich, low glycemic index (GI) fruits and vegetables, foods rich of good Omega 3 fat, fresh herbs and spices that reduce inflammation like ginger, turmeric, green tea and nettles can help preventing inflammation. Increasing physical activity to reduce body weight, limiting stress, limiting exposure to chemicals, airborne irritants and heavy metals, are important in reducing chronic inflammation[88, 89].

Targeting NF-κB

Given the drastic and invariable effects of NF-κB on tumor development and progression, this factor and the signaling pathways involved in its activation are attractive targets for cancer prevention and therapy. Several NF-κB or IKK-B inhibitors such as PS-1145[90], BMS-345541[91], dehydroasocorbic acid (DHA)[92], and N-acetyl-L-cysteine (NAC)[93] are under development[16, 94].

Huang et al showed that blockade of NF-κB activity in human prostate cancer cells inhibits angiogenesis, invasion, and metastasis by significantly inhibiting expression of VEGF, IL-8, and MMP-9[49]. Yemelyanov et al showed that PS1145 could inhibit both basal and induced NF-κB activity in prostate cancer cells. More importantly, they found that incubation with PS1145 inhibited the invasion activity of highly invasive PC3-S cells in a dose-dependent manner[95].

Biswas et al showed that Go6976, a well-characterized NF-κ B inhibitor, blocked EGF-induced NF-κ B activation and also caused breast cancer cells apoptotic death. Thus Go6976 and similar NF-κ B inhibitors are potentially novel low molecular weight therapeutic agents for treatment of ER- breast cancer patients[96]. Zhou and colleagues showed that inhibiting NF-kB pathway pyrrolidinedithiocarbamate (PDTC) could inhibit breast cancer cell, MCF7 sphere cell, proliferation and it also showed significant tumor growth inhibition in the mouse xenograft model[97].

Overall, these studies provided the framework for development of a novel therapeutic approach targeting NF-κB transcription factor to treat prostate cancer and breast cancer.

However, NF-κB signaling also plays an important role in immune function, and its absence or prolonged and substantial inhibition can result in severe immunodeficiency. This should be taken into consideration in cancer therapy.

Targeting ERK and p38MAPK Pathway

The nonsteroidal anti-inflammatory drugs (NSAID) R-flurbiprofen and ibuprofen have been shown to induce expression of p75NTR (neurotrophin receptor) in prostate cancer cell lines. p75NTR, a tumor necrosis factor receptor superfamily member, is a proapoptotic protein that functions as a tumor suppressor in the human prostate. NSAIDs induce p75NTR through activation of the p38 mitogen-activated protein kinase (MAPK) pathway, with a concomitant decrease in cell survival and migration[98].

Yong et al demonstrated the inhibitory effect of SB203580, a p38 MAPK inhibitor, on invasive and migratory phenotypes induced by actively mutated H-Ras and by TGF-b in MCF10A human breast epithelial cells[54].

Other targets

As mentioned before, IL-6 has been shown to stimulate the proliferation of prostatic carcinoma cell lines while blocking apoptosis induced by factors such as p53[51]. An investigation showed that anti-IL-6 mAb induced prostate tumor apoptosis and regression of xenografted human cancer cells in a nude mouse model[99].

Many other kinds of drugs that could target cancer-related inflammation — for example, chemokine-receptor antagonists and cytokine-receptor antagonists, and COX inhibitors — are in clinical trials. Phase I/II trials of antagonists of interleukin 6 (IL-6), the IL-6 receptor, Chemokine (C-C motif) ligand 2 (CCL2), C-C chemokine receptor type 4 (CCR4) and CXCR4 are underway for a range of epithelial and haematopoietic malignancies. The first (phase I/II) clinical trials of tumor necrosis factor-α (TNF-α) antagonists in patients with advanced cancer have resulted in disease stabilization and some partial responses[100–103].

Studies have highlighted that the treatment with nonsteroidal anti-inflammatory agents, such as COX-2 inhibitors, reduce the risk of developing certain cancers (such as breast and colon cancer) and the mortality caused by these cancers[104–107].

Summary

Here we have summarized and outlined the role of inflammation in breast and prostate carcinogenesis. Understanding how chronic inflammation is triggered how it contributes to the tumor progression and metastasis will be crucial for understanding tumor biology as well as the development of new therapeutic interventions. Although significant advances have been generated in our understanding of the effect of inflammation in tumor progression, challenges for the future are remained to translate these basic findings into clinical practice and arrive at novel treatment strategies that can regulate the inflammatory network to decrease their tumor-promoting properties, while increasing their tumor-suppressing or cancer cell-killing properties in cancer therapy.

Conflict of interest statement

No potential conflicts of interest were disclosed.

  • Received May 11, 2011.
  • Accepted June 9, 2011.

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