Host Effects on Human Neoplasia

1 Jun

Although Furth, Clifton, and their colleagues discovered an experimental basis for hormone de- pendency and responsiveness of endocrine neoplasms, their work was actually anticipated by the demonstration by Beatson (1896) that surgical removal of the ovaries in patients with advanced cancer of the breast caused a slowing of growth and even regression  in some cases. In 1941

Huggins and his associates (Huggins et al., 1941a,b) applied some of the principles suggested by Beatson’s study to the treatment of cancer of the prostate in human males. They noted that cas- tration and estrogen administration caused a prolongation of life in patients with prostate cancer, as well as changes and regression in the neoplastic gland itself. This led to a major area of clini- cal investigation  involving  the predictability  of the hormone  responsiveness  of several neo- plasms in the human and in animals, especially that of mammary carcinoma. The methodology involved in these studies concerns the measurement  of receptor proteins in cells that interact with steroid hormones (Figures 3.23 and 3.24). A somewhat more detailed diagram of the com- ponents and action of this hormone-receptor  complex may be seen in Figure 18.2. As noted in the figure, the estrogen receptor, a transcription factor (Figure 3.24) occurs in the cytoplasm in association with heat-shock proteins (hsp90) (Ylikomi et al., 1998) and immunophilin  chaper- ones (Pratt and Toft, 1997). Binding of estrogen leads to dissociation of the heat-shock proteins, receptor dimerization with an enhancement of phosphorylation of serine 167 in the estrogen re- ceptor protein (Castaño et al., 1998). The phosphorylated receptor dimer-ligand then enters the nucleus and, in association with several coactivators (Freedman, 1999), activates transcription of specific genes within the cell.

Those breast cancers in the human that exhibit moderate to elevated levels of the estrogen- receptor protein are usually found in more highly differentiated (lower-grade) carcinomas exhib-

Figure 18.2 Model of estrogen action mediated by the estrogen receptor. Estrogens enter cells by simple or facilitated diffusion and then bind to specific estrogen receptors. The estrogen receptor protein exists in an inactive state in the cytoplasm in association with heat shock protein 90 immunophilins  and other proteins (Pratt and Toft, 1997). Upon estrogen binding to the receptor, the receptor is freed from the other protein and undergoes phosphorylation  (p) and dimerization (Castaño et al., 1998). This complex enters the nucleus and, in association with other proteins  termed coactivators  (Freedman,  1999), binds to specific estrogen  response  elements  in target gene promoter  regions. Transcription of the estrogen-responsive gene then occurs with subsequent translation and formation of the protein product. (Modified from Kuiper et al., 1998, with permission of the authors and publisher.)

iting a relatively slow rate of cellular replication (Martin et al., 1979). Furthermore, patients with estrogen receptor–positive breast cancers usually experience longer survival after treatment than do patients with estrogen receptor–negative  neoplasms (Furmanski et al., 1980). Metastatic le- sions from primary breast cancers usually exhibit a lower level of estrogen-receptor  proteins than the primary lesions (Görlich and Jandrig, 1997). Interestingly, those carcinomas exhibiting Barr bodies (Chapter 10) in more than 10% of the tumor cells examined were much more likely to have high levels of the estrogen-receptor protein than those neoplasms exhibiting a lower pro- portion of Barr body–containing cells (Rosen et al., 1977).

Measurement of the estrogen-receptor  content of mammary neoplasms has demonstrated that the absence of such receptors usually predicts a lack of response to hormone therapy, that is, a lack of hormone responsiveness (Osborne and McGuire, 1978). Unfortunately, the presence of the receptor does not assure that the neoplasm will be hormone-responsive  but it does increase the chances of such an occurrence to about 1 in 2. Several studies in animals (King et al., 1976; Vignon and Rochefort, 1978) have also shown that the presence of estrogen-receptor proteins in mammary tumors does not necessarily confer an estrogen responsiveness to the growth of these neoplasms. However, the analysis of a second steroid hormone receptor, the progesterone recep- tor, has indicated that neoplasms exhibiting both estrogen and progesterone receptors have a rel- atively high degree of responsiveness,  usually 70% to 80% of the cases (cf. McGuire  et al.,

1978). Responsiveness to endocrine therapy may occur in a variety of ways, including modifica- tion of the internal hormonal milieu of the host by surgical adrenalectomy or hypophysectomy, the administration of androgens or large doses of estrogens or, during the last two decades, ad- ministration of antiestrogens (cf. Jensen, 1981). Responsiveness to these various types of endo- crine therapy as a function of the presence or absence of the estrogen and progesterone receptors is shown in Table 18.1. Interestingly,  estrogen receptor–negative  neoplasms  are usually more responsive  to cytotoxic chemotherapy  in metastatic breast cancer than are neoplasms  that are estrogen receptor–positive  (Lippman et al., 1978). In contrast, the presence of the estrogen re- ceptor may impart a poorer prognosis for young women with breast cancer (Aebi et al., 2000). As noted above, estrogen receptor–positive  breast cancers are more often diploid than are their negative counterparts, and their proliferative activity is inversely related to the estrogen receptor content, as noted above (Raber et al., 1982). As an additional variable, estrogen receptor–nega- tive breast cancers that do not express the epidermal growth factor receptor (EGFR) are usually more responsive  to primary  endocrine  therapy  than those expressing  EGFR (cf. Robertson,1996). Thus, in general, one may conclude that estrogen receptor–negative  breast cancers are further along in the stage of progression  than are estrogen  receptor–positive  breast cancers. While most of the epidemiological  risk factors for estrogen receptor–positive  and estrogen re- ceptor–negative  or –deficient breast cancers were similar, one striking difference was that the

Table 18.1 Response to Endocrine Therapy in Patients as a Function of the Presence (+) or Absence (–) of the Estrogen Receptor (ER) and Progesterone Receptor (PR)

late age at first full-term pregnancy was a risk factor for estrogen receptor–rich breast cancer but not for estrogen receptor–poor breast cancer (McTiernan et al., 1986).

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