Hormonal Carcinogenesis

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It was Furth9 who first tentatively suggested that hormones might be directly carcinogenic not by a genotoxic mechanism per se but by influencing the rate of cell division and thereby increasing the potential for spontaneous mutations. Drawing partially on the work of others, he suggested that while DNA molecules replicate, some copying "mistakes" might go unrepaired. In fact, the chromosomal instability at mitosis, could "produce cells carrying new karyotypes," which "are potential ancestors of novel clones liable to become malignant tumors."9 Furth9 went on to describe five lines of evidence to support the hypothesis of carcinogenesis without an extrinsic, genotoxic carcinogen. This evidence drew heavily on his own experience with thyroid carcinogenesis in the rat.

During the early 1970s, MacMahon and col-leagues10 published a series of papers suggesting that estrogens, generally, and estradiol, specifically, could be involved in human breast cancer carcinogenesis. At the same time, there was widespread scientific interest in the publication of data from Spiegelman's laboratory11 demonstrating a microscopically, and immuno-

logically, identifiable murine mammary tumor virus or type B virus in human breast milk. We undertook our first epidemiological study of breast cancer in young women to address the possibility that a transmissible agent causing breast cancer might also exist in human breast milk. We were unable to substantiate this hypothesis as there was no evidence of excess risk associated with breast-feeding, and the excess familial risk of breast cancer was seen in both the paternal and the maternal family trees.12 However, we were very impressed with the evidence supporting a role for endogenous estrogen and the key importance of age at menarche as an expression of this susceptibility. Over the subsequent 25 years, we as well as others13,14 have continued to utilize epidemiological and sero-logical studies to accumulate evidence that endogenous estrogens played a pivotal role in breast cancer.15 At the same time, it became increasingly clear that endogenous hormones were likely to be important in the etiology of other hormone-related cancers, including those of the testes, ovary, endometrium, prostate, and thyroid. In the mid-1970s, there was a sudden increase in the incidence of endometrial cancer; and in a series of epidemiological studies,16 it became clear that this "epidemic" was caused by the introduction and subsequent widespread use of estrogen-replacement therapy. Perhaps more definitively than any laboratory experiment, this epidemic demonstrated the critical role of estrogen in endometrial cancer causation and the relationship between hormone-induced increased cell proliferation and the evolution of cancer.15 It was also obvious that there was no other extrinsic carcinogen necessary or involved in this epidemic. In other words, the traditional two-stage initiator-promoter paradigm of carcinogenesis did not apply in this model of hormonal carcinogenesis.

In 1982, we published our first paper15 attempting to synthesize the experimental and human data into a coherent model of hormonal carcinogenesis (Fig. 1.1). There was, however, a paucity of convincing evidence on the precise relationship between specific hormones and risk of cancer in specific target organs. In general, measurement of circulating sex steroid hormones, such as estrogen, is complicated by individual, day-to-day, and laboratory variations.

Figure 1.1 The endogenous hormones (sex steroids or pituitary peptides) that are responsible for the growth and development of the relevant end organ, e.g., breast, thyroid, prostate are the same hormones that, by causing cell proliferation in the end organ, predispose that end organ to the development of a malignant phenotype.

Figure 1.1 The endogenous hormones (sex steroids or pituitary peptides) that are responsible for the growth and development of the relevant end organ, e.g., breast, thyroid, prostate are the same hormones that, by causing cell proliferation in the end organ, predispose that end organ to the development of a malignant phenotype.

Seldom were results from one laboratory readily comparable to those from another, and inconsistency of findings relating hormones to cancer risk became the norm. However, in recent years, there has been a series of prospective studies supporting a direct association between circulating estrogen levels and breast cancer risk. A meta-analysis of breast cancer and serum estrogen levels was published by Thomas et al.17 There was an average 16% higher level of the most bioac-tive estrogen, estradiol, in patients with breast cancer than in unaffected women (p = 0.0003).

An important concept related to human studies of hormonal carcinogenesis has evolved from observations such as those of Thomas et al.17 that mean differences in circulating sex steroid levels associated with increased cancer risk are typically not large. Pike18 made the critical observation that the age-specific incidence curve of breast cancer, as well as endometrial and ovarian cancers, fit the log incidence/log age model of Cook et al.19 once an effect of menopause was figured into the model. Based on such a model, small differences in serum hormone levels, since they are present virtually constantly, over a lifetime can be shown mathematically to predict substantial changes in cancer risk. Thus, a 20% difference in a particular trophic hormone could translate into a two- to threefold lifetime increase in risk of a particular cancer, the actual value depending on the constant associated with the age-specific incidence of that cancer. This observation is of critical importance as we evaluate the magnitude of the effect of sequence variants in genes associated with steroid hormone biosynthesis or metabolism.

A second, and arguably relevant, concept related to human studies of hormonal carcinogen-esis has gradually emerged from studies of the epidemiology of prostate cancer.20 A series of prospective studies of circulating testosterone (T) and dihydrotestosterone (DHT) did not show the same consistent relationship of higher serum androgen levels and prostate cancer risk.21 In their meta-analysis, Eaton et al.21 concluded the following:

This quantitative review reveals no convincing evidence that serum levels of endogenous sex hormones, their precursor compounds and metabolites and related binding protein, differ between men who subsequently go on to develop prostate cancer and those who do not.

Even more striking has been the observation that African Americans, who have the highest risk of prostate cancer, do not have the highest levels of circulating T or DHT.22,23 A seminal observation by Ross et al.20 demonstrated that Japanese men, who have a low risk of prostate cancer, have lower circulating levels of 3a,17jS-androstanediol glucuronide, which derives from the intraprostatic metabolism of DHT, the major androgen in the prostate that binds to the androgen receptor. Thus, the most relevant measure of the bioactive steroid (e.g., estradiol, DHT) or polypeptide (e.g., follicle-stimulating hormone, luteinizing hormone) hormone is at the cellular level, where ligand binding to a specific receptor occurs; and this may or may not be well represented by the measurement of such hormones in serum or

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