Susceptibility and chemoprevention Molecular Pathways

Chemo Secrets From a Breast Cancer Survivor

Breast Cancer Survivors

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There are numerous factors and molecular events that can increase or decrease the susceptibility toward developing breast cancer. Understanding the molecular basis of this disease often relies on identifying the signal transduction pathways whose activation (or inhibition) directly regulates the development of breast cancer or acts as a marker for breast cancer susceptibility or protection. Once these pathways are identified, development of chemopreventative strategies to decrease the risk of breast cancer and chemotherapeutic regimens to treat existing cancers will be greatly facilitated.

p53 is a tumor suppressor protein that when activated acts as a transcription factor to induce expression of a host of genes involved in responses to DNA damage (triggered by ultraviolet light, ionizing radiation, or carcinogenic chemicals) (6,10). The central function of p53 is to induce cell cycle arrest and decide if DNA damage can be fixed (arrest followed by resumption of the cell cycle), or is irreparable (activation of the apoptotic pathway). p53 thus plays a critical role in preventing genotoxic initiation of precancerous lesions. Mutation of the p53 gene or loss of p53 responsivity is one of the most common events identified in human breast cancer (detected in ~50% of cases), and loss of the p53 allele in mouse models predisposes them to cancer. In fact, transformation of normal ductal epithelium to DCIS typically progresses to the formation of a malignant, invasive cancer of the breast, and is frequently linked to mutation of p53 (2). p53 can be sensitized, i.e., made more responsive, by the pregnancy hormones estrogen and progesterone (11) and many dietary phytochemicals (12). Sensitization of p53 minimizes cancer initiation by increasing the likelihood that cells with activated p53 will either repair damaged DNA, or will be removed by apoptosis.

The estrogen biosynthetic and signaling pathways have been very well studied in normal development of the breast (i.e., directing proliferation of ductal epithelial cells during puberty), as well as in breast cancer (13). The enzyme aromatase (itself a popular target of estrogen responsive breast cancer) (14,15) converts androgen into estrogen, produced distally by the ovaries and locally in the breast. Estrogen is highly mitogenic, and directs cell proliferation by binding to estrogen receptors and activating transcription. Estrogen also may ultimately lead to the release of epidermal growth factor (EGF), itself a mitogenic factor, and may be converted into hydroxylated estrogens which in turn can act to stimulate cell division. Inappropriate signaling through the estrogen response pathway can lead to unchecked cell proliferation, and breast cancer.

Upregulation of signaling through the aryl hydrocarbon receptor (AhR) has recently been closely linked with breast cancer initiation, likely by inducing hyperplasia in epithelial breast tissue. Environmental toxins such as dioxin bind to cytosolic AhR, which then acts as a transcription factor to induce the expression of several genes, including the monooxygenase CYP1A1. Protoxins are then metabolized into mutagenic substances by CYP1A1. With respect to breast cancer specifically, CYP1A1 is capable of generating hydroxylated estrogens (i.e., 16a-hydroxyestrone) with mitogenic activity, and variant or increased CYP1A1 activity is associated with an increased risk of breast cancer (16). Additionally, AhR activation leads to the upregulation of other genes that regulate the antioxidant response and the cell cycle.

Many phytochemicals have been shown to modulate AhR activation and CYP1A1 expression and activity, including polyphenols, flavonoids, and phytoalexins, and may have a role in breast cancer prevention.

Signaling by growth factors [such as insulin-like growth factor (IGF), vascular endothe-lial growth factor (VEGF), transforming growth factor beta (TGF-b), and EGF represents an important area of focus in cancer initiation and development. Increased signaling through IGF can inhibit apoptosis (likely by upregulating the protein kinase Akt and the transcription factor NF-kB) (17), and some correlation exists between high circulating blood levels of IGF and the risk of premenopausal breast cancer (18). Epithelial growth factor, signaling through its receptors epidermal growth factor receptor (EGFR) and HER-2/neu plays a significant role in stimulating cell proliferation in the mammary gland (19). Vascular endothelial growth factor expression is regulated by NF-kB as well as cyclooxygenase and lipoxygenase metabolites of arachidonic acid (AA), and signaling it increases the growth and migration of endothelial cells that leads to vascularization of growing tumors (20). In contrast, TGF-b acts as a negative regulator of cell growth, as disruption of TGF-b signaling is correlated with cancer development (21). Additionally, crosstalk amongst growth factor signaling networks exists. For example, both IGF and EGF are capable of regulating the expression of VEGF. Antagonistic effects are also seen. IGF activation can down regulate TGF-b signaling (22), while TGF-b can decrease the circulating levels of IGF. Modulation of growth factor signaling obviously represents a complex yet important area of research in the development of chemopreventative strategies.

The aberrant metabolism of arachidonic acid by cyclooxygenases (COX) and lipoxy-genases (LO) has recently been shown to be a predictive marker for initiation and progression

Figure 11.1 Signaling pathways which promote cell growth, survival, and metastasis and stimulate angiogenesis (dark grey) exist in a balance with signals that suppress growth, sensitize cell to apoptosis, and induce differentiation (light grey). Chemopreventive agents appear to have common overlapping roles in their ability to control growth signals through TGF beta family signaling, inhibit cyclooxygenase activity, regulate IGF, control oxidation, and sensitize or activate p53. (RA = retinoic acid, TAM = tamoxifen, NSAID = nonsteroidal antiinflammatory drug)

Figure 11.1 Signaling pathways which promote cell growth, survival, and metastasis and stimulate angiogenesis (dark grey) exist in a balance with signals that suppress growth, sensitize cell to apoptosis, and induce differentiation (light grey). Chemopreventive agents appear to have common overlapping roles in their ability to control growth signals through TGF beta family signaling, inhibit cyclooxygenase activity, regulate IGF, control oxidation, and sensitize or activate p53. (RA = retinoic acid, TAM = tamoxifen, NSAID = nonsteroidal antiinflammatory drug)

of a variety of cancers, and has been correlated with ultimate outcome in patients with breast cancer. COX-2 upregulation was first associated with a predisposition for colon cancer development, and COX-2 expression and activity are increased in breast cancer cells (23). The upregulation of COX-2 is indicative of, and is at least partially responsible for, increased cell growth and migration and decreased apoptotic rate. The AA metabolizing enzymes 5-lipoxy-genase and 12-lipoxygenase are also overexpressed in many cancerous tissues, while decreased expression of 15-lipoxygenase is observed in many carcinomas. Recent studies have correlated increased expression of COX-2, 5-LO, and 12-LO with poor clinical outcome of breast cancer patients (24—26). Pharmacological COX inhibitors are currently in clinical trials as chemopreventative or chemotherapeutic agents (27), and the discovery and application of plant derived inhibitors of COX and LO represent an intense area of scientific and clinical research (28).

Many plant derived compounds either have been shown, or offer promise, to act as chemopreventative agents that block the development of breast cancer (29). These phytochemicals include but are not limited to the flavonoids, catechins, lignans, (poly)phenolics, and organosulfones. Interestingly, a subset of these phytochemicals act on multiple signaling pathways to coordinately suppress breast cancer initiation and progression, often by acting on a common signaling intermediate. Additionally, many of these plant derived compounds exert their protective effects by acting as antioxidants, which minimize oxidative stress and DNA damage. Several of the specific signaling pathways through which phytochemopreventative agents are known to act are detailed in the following (Figure 11.2).

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