Estrogens And Their Involvement In Carcinogenesis

Estrogens are a family of related steroidal molecules that stimulate the development and maintenance of female characteristics and sexual reproduction, including regulation of the menstrual cycle, and have several other physiological functions. The most prevalent forms of human estrogens are estradiol and estrone, which are produced and secreted by the ovaries, although estrone is also synthesized in the adrenal glands and other organs.

Estradiol

Estrone

Estradiol

Estrone

FIGURE 3.1 Sequence of events related to steroid hormone activity.

The estrogen receptor (ER) is a ligand-dependent transcription factor, that is, a DNA-binding protein that regulates the transcription of its target genes. Although early models proposed that the ERs were cytoplasmic and were translocated to the nucleus after binding to the estrogen molecules, subsequent studies with monoclonal antibodies revealed that the ERs were located in the nucleus.

Regulation of gene transcription by estrogens is highly complex. It involves regions of DNA called estrogen response elements (EREs) and also the binding of several nuclear proteins (coactivators) that form a multisubunit transcriptional complex. Occupation of the steroid binding domain in the receptor by the hormone is followed by receptor dimerization, which is essential for DNA binding. On estrogen recognition, a conformational change takes place in the receptor protein that allows the recognition of coactivators and the start of the transcription process.

The natural estrogens induce tumors in a variety of organs in laboratory animals, and high estrogen levels increase the risk of breast and uterine cancer.1 Several mechanisms have been proposed that explain the development of estrogen-dependent tumors. In the first place, the transcription process initiated by the binding of estrogens to their receptors ultimately induces cell proliferation in some target tissues. Examples are breast tissue, where estrogens trigger the proliferation of cells lining the milk glands, thereby preparing the breast to produce milk in case of pregnancy, and the endometrium of the uterus, where they stimulate cell proliferation in order to prepare the uterus for implantation. This proliferative action is one of the physiological roles of estrogens, but it can also lead to the development of breast or uterine cancer because if cells from these tissues already possess a DNA mutation that increases the risk of developing cancer, they will proliferate (along with normal cells) in response to estrogen stimulation.

An alternative mechanism that explains the carcinogenesis by estrogens is the generation of mutagenic species in their metabolism.2 Strong evidence supports that tumors may be initiated by metabolic conversion of estradiol (E2) to the catechol metabolite 4-hydroxyestradiol (4-OHE2), which is further oxidized to estradiol-3,4-quinone (E2-3,4-Q) (Fig. 3.2).

Estradiol-3,4-quinone reacts with DNA as a Michael substrate forming a bond between its C-1 atom and the N-7 atom of guanine, affording hydroquinone 3.1. The positive charge generated at the guanine N-7 position facilitates the hydrolysis of the glycosidic bond of 3.1, leading to the purine derivative 3.2 and depurinized DNA (3.3) (Fig. 3.3).

Alternatively, the nucleophilic attack to the estradiol-3,4-quinone may involve the N-3 atom of adenine residues, leading to hydroquinone 3.4. Similarly to 3.1, these covalent adducts are unstable under hydrolytic conditions and evolve to give purine derivatives 3.5 and depurinized DNA 3.3 (Fig. 3.4).

As shown in Fig. 3.5, the alternative catechol metabolite 2-hydroxyestradiol (2-OHE2) produces the estradiol-2,3-quinone (E2-2,3-Q), which also gives DNA adducts by forming a covalent bond with a nitrogen atom of a purine base, but these adducts are much less reactive than those derived from E2-3,4-Q and have less relevance in the carcinogenesis due to estradiol.3

The link between ovarian function and breast cancer has been known for more than a century, and endocrine therapy can be considered as the oldest, safest, and best-established systemic treatment for breast cancer. Many breast and endome-trial tumors are estrogen-dependent, and for this reason their treatment is based on the modulation of these hormones. This can be achieved directly by h3coh

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