Genetic Basis Of Hormonal Carcinogenesis

The identification and genetic characterization of families at high risk of breast cancer is the most striking example of the potential importance of inherited traits in breast cancer causation. The localization and sequencing of BRCA1 and BRCA2 has provided two important genes contributing to familial breast and ovarian can-cer.24,25 Somewhat surprisingly, mutations in these genes, which appear to be classic tumor-suppressor genes, seem to contribute little, if at all, to the causative pathway of sporadic breast cancer. Likewise, mutations in two other tumor-suppressor genes, TP53 and AT, contribute to breast cancer risk in certain families but, again, not generally to the risk of sporadic breast can-cer.26

The focus of much current breast cancer research is on susceptibility and progression, until the hormone-independent stage, by endogenous hormone stimulation (Fig. 1.2). Under the majority of circumstances, we assume that a breast epithelial cell does not contain a germline mutation in a tumor-suppressor gene such as BRCA1. In response to circulating steroids, (e.g., ovavian estradiol and progesterone) there is an accumulation of cell divisions in breast epithelium over many years. Each cell division carries a certain risk of a DNA copying error that is not corrected,

Figure 1.2 Estradiol and, to a lesser degree, other steroid hormones (e.g., progesterone) drive breast cell proliferation, which facilitates mutation, enhances fixation of mutations, or facilitates expression of genetic errors by loss of heterozygosity by defects in DNA repair. Germline mutations in relevant tumor-suppressor genes accelerate the transformation to the malignant phenotype.

Figure 1.2 Estradiol and, to a lesser degree, other steroid hormones (e.g., progesterone) drive breast cell proliferation, which facilitates mutation, enhances fixation of mutations, or facilitates expression of genetic errors by loss of heterozygosity by defects in DNA repair. Germline mutations in relevant tumor-suppressor genes accelerate the transformation to the malignant phenotype.

and some of these are eventually relevant to the constellation of such mutations needed to produce the malignant phenotype. Ovarian steroid hormones drive the process of cell division directly and are, thus, the primary carcinogens. The amount of ovarian steroid hormones produced during each menstrual cycle is under strong genetic control, and the relevant genes are those in the relevant sex steroid biosynthesis and metabolism pathway (Table 1.1). We assume that there are common (>1%) sequence variations in these genes, which can produce meaningful differences in total ovarian steriod "exposure" over a woman's lifetime. Of course, the same, or novel, sequence variants in these genes can be associated with the progression of hormone-related cancers, as has been well documented for variants in the androgen receptor gene.20 The details of the endocrine pathways and the relevant candidate genes will be discussed by several of the chapters in this book, so further details are not provided here. A list of some candidate endocrine genes is provided in Table 1.1, and common variants in a broader set of genes are under investigation (see Chapter 4). The important feature of this paradigm is that the candidates are predictable because they encode proteins that are part of known physiological and cellular pathways. More candidate genes will certainly emerge as we begin to understand more about the relevant signaling and transport pathways in steroid-responsive cells. One important example of such nonendocrine factors is the growth hormone family, such as insulin-like growth factor-1 and related compounds, which are discussed in Chapter 5.

With the sequencing of the human genome and the development of high-throughput DNA sequencing and genotyping technologies, there has been a rapid expansion in such studies of complex traits and multigenic diseases. The future holds considerable promise for defining genetic pathways and developing targeted diagnostic and therapeutic approaches to the hormone-related cancers.

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