MECHANISTIC CONSIDERATIONS IN HORMONAL CARCINOGENESIS

25 May

Since all hormones are chemicals, their induction of neoplasia might be considered in the same light as chemical carcinogens discussed earlier (Figures 3.1, 3.3, 3.21, and 3.22). However, there is substantial evidence that, with few exceptions,  the carcinogenic  action of hormones is inti- mately associated with their hormonal activity. Thus, in determining the mechanism of carcino- genesis by hormones,  it is important  to consider  the mechanisms  by which these chemicals induce their hormonal effects on cells and tissues.

Unlike most chemical carcinogens, hormones in general need not be metabolized to exert their hormonal  effects on cells. Rather, in all known instances,  hormonal  effects on cells are mediated through direct interaction of the hormone with a specific receptor molecule. A simpli- fied diagram of the location of such receptors in cells is seen in Figure 3.23. In general, hormone receptors may occur either as soluble proteins dissolved in the internal milieu of the individual cell or as complex, membrane-associated  glycoproteins whose initial action is primarily at the external plasma membrane. Low-molecular-weight  hormones such as steroids and the thyroid hormone interact with intracellular receptors, producing a complex that, when transported into the nucleus by itself or complexed with other proteins, alters in a specific manner the transcrip- tion of certain genes. The soluble intracellular receptors for these molecules share a common set of structural motifs. A diagram of the structure of a number of these receptors can be seen in Figure 3.24 (cf. Vedeckis, 1992). The commonality of these receptors involves a modulating do- main that is relatively unconserved among these various different receptors and is probably in- volved  in the transcriptional  regulation  of gene expression.  The “DNA-binding  domain” interacts specifically with DNA response elements having specific sequences. This is the most highly conserved region of all of this superfamily of receptors. The carboxyl terminal region is designated the ligand-binding  domain, which interacts specifically with the appropriate ligand (hormone) with high affinity and specificity. This domain also has a high degree of conservation within the superfamily, although not as exact as the DNA-binding domain. Thus, the ligand or hormone reacts with the receptor and in so doing causes an “activation” of the receptor, enabling it to interact with the specific DNA sequences (promoter) within DNA. This activation involves

Figure 3.23 Location of receptors in cells. Receptor locations are as follows: peptide hormones such as insulin,  growth  hormone,  gonadotropins,  thyrotropin,  parathyroid  hormone,  and corticotropin  in plasma membrane; steroid hormones such as aldosterone, cortisol, estradiol, progesterone,  testosterone, and dihy- droxyvitamin  D3  in cytoplasm; and thyroid hormone in nucleus. cAMP indicates cyclic adenosine mono-phosphate; Ca++, calcium ion; and mRNA, messenger RNA. (Adapted from Kaplan, 1984, with permission of the author and publisher.)

a conformational change in the receptor that not only allows for the interaction with DNA of the complex but also separates the receptor, steroid hormone receptors in particular, from proteins termed heat-shock proteins, which may maintain the receptor in its native form in the absence of the ligand (hormone); however, retinoic acid and thyroid hormone receptors are not associated with heat shock proteins (cf. Reichel and Jacob, 1993).

The structure of membrane-bound  receptors is much more complex than the intracellular receptors described above. Receptors for neurotransmitters  and glycoprotein hormones usually have a number of transmembrane segments as well as an extracellular and cytoplasmic domain. Receptors for a variety of growth factors—including  growth hormone and prolactin, both hor- mones of the anterior pituitary—exhibit  a single transmembrane  domain with an extracellular and cytoplasmic domain as well. Examples of these two general types of receptors are indicated diagrammatically  in Figure 3.25A and B. In all cases the ligand (hormone,  neurotransmitter, growth factor)-binding domain is the extracellular component of the structure. The cytoplasmic domain in the case of the glycoprotein hormone-neurotransmitter type of receptor interacts di- rectly with a transducing G protein (Reichert et al., 1991; Premont et al., 1995). A functionally

Figure 3.24 Structure of nuclear receptors. Nuclear receptors comprise three domains. The amino ter- minal region, called the “modulating  domain,” is not conserved among the superfamily  of nuclear recep- tors, is of varying length, and may contain sequences that are involved in the transcriptional  regulation of gene expression  (transactivation).  The second region is the “DNA-binding  domain” that interacts specifi- cally with DNA response element via two cysteine zinc fingers. It is the most highly conserved region of the nuclear receptors. The carboxyl terminal region is the “ligand-binding  domain” that binds the appropri- ate ligand with high affinity and specificity. It is also quite conserved among nuclear receptors, although less so than the DNA-binding domain. The numbers in the DNA- and ligand-binding domains represent the per- centage  of amino acid identity  in these regions,  compared  to those in the glucocorticoid  receptor  (GR). Other receptors diagrammed  are the mineralocorticoid  (aldosterone)  receptor (MR), progesterone  receptor (PR), androgen receptor (AR), estrogen receptor (ER), thyroid hormone receptor (TR), retinoic acid receptor (RAR), and vitamin D receptor (VDR). (From Vedeckis, 1992, with permission of the author and publisher.)

similar pathway occurs with the hormone and growth factor receptors exhibiting a single trans- membrane domain but differs in that the cytoplasmic domain either possesses inherent protein tyrosine kinase activity, which is activated by interaction of the receptor with its ligand, or inter- acts with a cytoplasmic protein kinase upon interaction with ligand. For those monomeric recep- tors in Figure 3.25B, interaction with the ligand results in dimerization or trimerization (Heldin,1995) of the single molecules,  facilitating  activation  of the protein kinase either inherent or present in the cytoplasm. Dimeric receptors such as the structure seen in the center also occur— e.g., insulin or insulin growth factor-1 receptors, wherein activation of the inherent kinase only requires interaction with the ligand. Activation of these protein kinases results in further protein phosphorylations mediated through transducing G proteins (Chapter 7), thus allowing a “signal” to pass from membrane to the nucleus (Chapter 7) (Linder and Gilman, 1992). Hormone recep- tors with single transmembrane domains whose ligands include growth hormone, prolactin, and a number of peptide hormones and growth factors for lymphoid and hematopoietic tissues ini- tiate signal transduction by association with specific cytoplasmic kinases that are not an integral part of the receptor molecule (cf. Kelly et al., 1994; Carter-Su et al., 1994).

The ultimate effect of the hormonal signal is the regulation of gene expression, probably by the interaction of proteins activated through the signal transduction pathway, and these in turn interact directly with specific sequences in the DNA. This has been shown for a cyclic AMP response element-binding protein (CREB) that interacts directly with a sequence in DNA known as CRE (cyclic AMP response element) (Lu et al., 1992). The initial signal between the growth factor and/or hormone and its receptor is limited by endocytosis of the complex into the cyto- plasm, where the ligand is separated and destroyed while the receptor is recycled to the cell sur-

Figure 3.25A Model of glycoprotein  hormone  receptors.  Schematic  view of the membrane  insertion and the coupling to the signaling complex. The receptors consist of a single polypeptide chain with a large extracellular  amino terminal domain. The transmembrane  domain is made up of 7 transmembrane  helices with extracellular connecting loops E-I, E-II, and E-III (between helices 2 + 3, 4 + 5, 6 + 7) and cytoplas- mic connecting loops C-I, C-I, and C-III (between helices 1 + 2, 3 + 4, 5 + 6). The carboxy terminus ex- tends into the cytoplasm  (cytoplasmic  domain).  The connecting  loop C-III was proposed  to achieve the coupling of the receptors to a stimulating G-protein (GP) of the signaling complex (AC, adenylyl cyclase). (From Merz, 1992, with permission of the author and publisher.)

face (cf. Dautry-Varsat and Lodish, 1984). However, for the initial signal from the interaction of the receptor with its ligand to occur, a highly specific interaction is necessary, comparable to the specific interaction  of a steroid or thyroid hormone with its intracellular  receptor. Thus, hor- mones in their native state induce changes in the expression of DNA within cells; in many in- stances  this results in an increased  proliferation  of the target cell. Growth  factors  may be considered as polypeptide hormones with a more general target population than specific endo-

Figure 3.25B General structural features of receptors exhibiting  a single transmembrane  domain. The horizontal  gray line represents  the plasma  membrane,  and structures  below  this line are cytoplasmic. Hatched regions represent  cysteine-rich  repeat domains and closed boxes demarcate  the protein tyrosine kinase domains. Horizontal lines connecting vertical structural components of the receptor represent disul- fide bridges. KIN = protein kinase distinct from the receptor.

crine tissues targeted  by polypeptide  pituitary  hormones.  Growth factors, G proteins,  signal transduction, and their role in neoplasia are discussed later in the text (Chapter 7).

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