The role of genetics in estrogen responses: a critical piece of an intricate puzzle

Abstract

The estrogens are female sex hormones that are involved in a variety of physiological processes, including reproductive development and function, wound healing, and bone growth. They are mainly known for their roles in reproductive tissues--specifically, 17β-estradiol (E2), the primary estrogen, which is secreted by the ovaries and induces cellular proliferation and growth of the uterus and mammary glands. In addition to the role of estrogens in promoting tissue growth and development during normal physiological states, they have a well-established role in determining susceptibility to disease, particularly cancer, in reproductive tissues. The responsiveness of various tissues to estrogen is genetically controlled, with marked quantitative variation observed across multiple species, including humans. This variation presents both researchers and clinicians with a veritable physiological puzzle, the pieces of which--many of them unknown--are complex and difficult to fit together. Although genetics is known to play a major role in determining sensitivity to estrogens, there are other factors, including parent of origin and the maternal environment, that are intimately linked to heritable phenotypes but do not represent genotype, per se. The objectives of this review article were to summarize the current knowledge of the role of genotype, and uterine and neonatal environments, in phenotypic variation in the response to estrogens; to discuss recent findings and the potential mechanisms involved; and to highlight exciting research opportunities for the future.

Keywords: genotype; reproductive tissue.

Figure 1.

Genetic control of uterine growth in response to E₂. The increase in uterine peroxidase activity in sexually immature inbred strains of mice at 24 h after 3 daily injections of E₂. (See ref. for additional information).

Figure 2.

Apoptosis in uterine epithelium 72 h after treatment with E₂. A) Localization of TUNEL-positive cells (brown, TUNEL-positive; blue, hematoxylin). B) Quantity of CC3 expression in uterine epithelia of B6, C3H, and B6C3 mice. (See ref. for additional information).

Figure 3.

Genetic control of the change in vaginal area in response to E₂. A) Images depicting vaginal area of vehicle- and E₂-treated B6 and C3H mice. B) Quantification of vaginal area 10 d after vehicle or E₂ treatment. Letters above bars indicate differences in the vaginal area between strains; P < 0.05. There was also a strain-by-treatment interaction; P < 0.01 (unpublished results).

Figure 4.

Genetic control of mammary ductal growth and side branching in response to E₂. Mammary ductal length and side branching were measured 3 d after 2 daily injections of E₂. Letters above bars indicate differences in the ductal length or total branches between strains; P < 0.05. (See ref. for additional information).

Figure 5.

Proliferation and apoptosis in mammary epithelium in response to estrogen. Quantification of Ki-67 and CC3 in mammary epithelia of B6 and C3H mice 72 h after treatment with E₂. Letters above the bars indicate differences in the Ki-67- or CC3-positive cells between strains; P < 0.05. (See ref. for additional information).

Figure 6.

ER structure and molecular mechanism. A) Domain structure of ER. From the amino terminus (N) to the carboxy terminus (C), the ER contains 6 domains: A, B, C, D, E, and F. The A/B domain contains one of the transcriptional AFs (AF1). The C domain contains the DBD. Domain E binds to estrogen ligands, with critical helix 12 (H12) mediating interactions with transcriptional coregulators. This ligand-dependent activity defines AF2. B) Mechanism of ER-mediated transcriptional regulation. Access of ER to ERE motifs is facilitated by pioneer factors such as FoxA1. E₂ binds to the ER, which leads to recruitment of coactivators and chromatin remodelers. Increased histone acetylation makes chromatin more accessible and allows RNA polymerase II (RNA Pol II) to access target gene transcription start sites (TSS).

Figure 7.

Effect of POO on the uterine response to E₂ in female mice. Letters above bars indicate differences in the E₂-induced increase in uterine weight between strains; P < 0.05 (unpublished results).