Estrogens and the risk of breast cancer: A narrative review of literature

Abstract

In female mammals, the development and regulation of the reproductive system and non-reproductive system are significantly influenced by estrogens (oestrogens). In addition, lipid metabolism is another physiological role of estrogens. Estrogens act through different types of receptors to introduce signals to the target cell by affecting many estrogen response elements. Breast cancer is considered mostly a hormone-dependent disease. Approximately 70% of breast cancers express progesterone receptors and/or estrogen receptors, and they are a good marker for cancer prognosis. This review will discuss estrogen metabolism and the interaction of estrogen metabolites with breast cancer. The carcinogenic role of estrogen is discussed in light of both conventional and atypical cancers susceptible to hormones, such as prostate, endometrial, and lung cancer, as we examine how estrogen contributes to the formation and activation of breast cancer. In addition, this review will discuss other factors that can be associated with estrogen-driven breast cancer.

Keywords: Breast cancer; ER; Estrogen; Oestrogen; Risk.

Fig. 1

Signaling Pathway of Estrogen Receptor. Estrogen can cross the plasma membrane, where it interacts with intracellular ER and ER to affect DNA directly. The GPER1 and/or ER and ER can interact with estrogen to cause it, to activate intracellular signaling cascades as an alternative. Estrogen-mediated signaling events can be classified as genomic and non-genomic due to differences in the cellular and molecular processes regulating gene expression, in which estrogen-receptor complexes can bind to DNA directly or indirectly. The migration of estrogen-receptor complexes into the cell nucleus and direct contact with chromatin at particular DNA sequences known as estrogen response elements are two examples of genomic impacts (EREs). More than one-third of human genes controlled by estrogen receptors are reported to lack ERE sequence elements, although EREs have been found in multiple gene promoters and regulatory regions. Contrarily, non-genomic impacts entail the indirect control of gene expression via a range of intracellular signaling occasions. Below is a description of the known ways through which estrogens regulate both genomic and non-genomic aspects of gene expression.

Fig. 2

Estrogen synthesis pathway in the ovary and brain. (A) Synthesis of estrogens begins with the production of pregnenolone from cholesterol, catalyzed by the cytochrome P450 side-chain cleavage enzyme (P450scc). The pregnenolone is transformed into progesterone by 3 b-hydroxysteroid dehydrogenase (3 b-HSD) in both thecal and granulosa cells. Progesterone is transformed to androgens by cytochrome P450 17a-hydroxylase (P45017a) and 17 b-hydroxysteroid dehydrogenase (17 b-HSD) in the thecal cells throughout the follicular phase. The transformation of E2 is enhanced by the aromatase enzyme (P450Arom) in granulosa cells. (B) Neurons express all of the mandatory enzymes for the production of estrogen to create brain estrogen [12].

Fig. 3

Estrogen metabolism pathway in humans. The diagram shows the metabolism of estradiol and other natural estrogens such as estrone and estriol. It demonstrates that conjugation (e.g., sulfation and glucuronidation) occurs in the case of estradiol and metabolites of estradiol that have one or more available hydroxyl (–OH) groups. Catechol and quinone formation from estrone is shown and how the derivatives are reacting with DNA to form depurination DNA adducts (adapted from Ref. [16]).

Fig. 4

The five main subtypes of breast cancer; are where the best prognosis is when the ER is positive, while the worst is a triple-negative case when ER is negative. BioRender (2021). Intrinsic and Molecular Subtypes of Breast Cancer. Retrieved from https://app.biorender.com/biorender-templates/t-5f872409fb2c3900a82e109e-intrinsic-and-molecular-subtypes-of-breast-cancer.