Breast Biology

In adult humans, structures like the epidermis (^12) and the colon mucosa (^13) undergo a constant turnover, whereas others like the liver parenchyma (^16) and urothelium (^14) only proliferate significantly for the purpose of repair after damage. Breast tissue is different from all of these (Figure 18.1).

First of all, the organ does not develop fully before puberty, so there is one additional growth phase during the second decade of life. During puberty, the immature ducts elongate into the surrounding connective tissue to form 15-20 lobuli. This process involves multiplication of the ductal cells and an expansion of its stem cell population. The connective tissue in the breast likewise expands.

Then, for a period of up to 45 years, the ductular tissue undergoes regular monthly cycles of proliferation and apoptosis. In some women as many as 500 cycles take place, before cessation of ovulation and estrogen production in the ovaries induces menopause.

This regular cycling is interrupted by pregnancies during which the ducts extend further into the underlying connective tissue, where they branch and widen into alveoli. Concomitantly, the secretory cells differentiate and the ducts mature. After parturation, the gland produces substantial amounts of carbohydrates, fat and proteins secreted in the milk, potentially over several years. The secreted proteins provide nutrients, but also include growth factors and immunoprotective proteins.

Weaning induces a partial involution of the gland, again accompanied by apoptosis of glandular cells, particularly the luminal secretory cells in the alveoli. Once again, the tissue, epithelia and stroma alike, is remodeled.

These cycles are controlled by a combination of hormones and locally produced growth factors. The pubertal growth phase is stimulated by estrogens from the ovaries, which become active at this time, and by growth hormone and its 'somatomedin' mediators IGF1 and IGF2. The monthly cycles are controlled mainly by estradiol and progesterone, supported by insulin and further hormones. During the first phase of the monthly cycle, follicle cells secrete mostly estrogens. After release of the oocyte gestagens like progesterone are the major product. Unless fertilization takes place, the follicle degenerates and minimal estrogen and progesterone levels elicit an involution phase in the breast and, more pronounced, in the uterus endometrium. The pregnancy growth phase is stimulated by several hormones, including gestagens, estrogens, growth hormone and insulin, but also glucocorticoids and, of course, prolactin. As in other tissues, proliferation of epithelial cells in the breast is supported by the stroma. Stromal cells and epithelial cells both produce paracrine growth factors, partly in response to steroid hormones.

Figure 18.1 Growth phases of the breast

Estrogens represented by estradiol and gestagens represented by progesterone act on cells by binding to specific receptors which belong to the steroid hormone receptor superfamily (Figure 18.2). The superfamily encompasses a large number of DNA-binding proteins with a variety of ligands, e.g. the retinoic acid receptors (^■8.5, ^10.5). The estrogen receptors and the progesterone receptors belong to a group of more closely related receptors which also includes the androgen receptor (^■19.2). The members of this group are ligand-dependent transcription factors that bind as homodimers to specific symmetric binding sites on DNA. These are termed

Figure 18.2 Some members of the steroid receptor superfamily The androgen receptor (AR), estrogen receptors (ERa, ERP), a progesterone receptor (PRP), two retinoic acid receptors (RARa, RARP2), and the vitamin D receptor (VDR), and their subdomains are drawn to scale. Subdomains A/B and E/F are not separated in this representation (compare Figures 18.3 and 19.6).

Figure 18.2 Some members of the steroid receptor superfamily The androgen receptor (AR), estrogen receptors (ERa, ERP), a progesterone receptor (PRP), two retinoic acid receptors (RARa, RARP2), and the vitamin D receptor (VDR), and their subdomains are drawn to scale. Subdomains A/B and E/F are not separated in this representation (compare Figures 18.3 and 19.6).

ERE (estrogen-responsive element), PRE (progesterone-responsive element), ARE (androgen-responsive element), etc.

The estrogen receptor a (ERa) is a typical representative (Figure 18.3). Its DNA-binding domain, which contains two zinc fingers, is located at the center of the primary amino acid sequence. It is flanked on the N-terminal side by a transactivation domain, designated as activation function 1, AF-1. A hinge region on its C-terminal side connects a second transactivation domain, named AF-2. The AF-2 domain binds the ligand and its activity is strongly dependent on ligand-binding. Moreover, protein interactions exerted by this domain control the receptor activity overall.

Inactive receptors are retained in the cytosol and become capable of entering the nucleus only after binding of the ligand and an ensuing conformation change. Some receptors are bound by heat shock proteins like HSP90, others are free, but are shuttled rapidly out of the nucleus, unless occupied by an agonistic ligand. After binding to their specific recognition sites on DNA, the receptor dimers recruit various co-activator proteins through their AF domains. The AF-2 domain of the ERa is known to bind at least five different co-activator proteins specifically. The best characterized of these is the SRC1 (steroid receptor co-activator) protein. Co-activators mediate the interaction between steroid hormone receptors and the general transcription apparatus and the modification of chromatin at the binding site. Binding of co-activators stimulates histone acetylation and the actual initiation of transcription. In addition, they integrate signals from several transcription factors binding to the regulatory regions of the same gene and from signal transduction pathways. For instance, certain co-activators interacting with the estrogen or androgen receptors are regulated by MAPK phosphorylation in response to growth factors of the EGF family. The receptor itself is also phosphorylated. While interactions with co-activators lead to gene activation, interactions with co-repressors can cause gene repression. Repression can be exerted by the ERa, but more pronounced by the progesterone receptor a.

Figure 18.3 Structural domains of the estrogen receptor a and their functions

A second mechanism of ERa action does not require binding of the receptor to DNA. Steroid hormone receptors can interact with several other transcription factors, either sequestering them or modulating their activity while they are bound to DNA. In this fashion, the receptors can regulate the activity of genes that do not possess canonical receptor binding sites. Specifically, the ERa can modulate the activity of API transcription factors. This may be the main mechanism by which estrogens stimulate cell proliferation, i.e. by mimicking activation of MAPK pathways (^6.2) alone or synergistically with growth factors (Figure 18.4). Additionally, estrogens stimulate the production of EGF-like growth factors in breast tissue.

The regulation of breast tissue growth and function by estrogens is in reality more complex than shown in Figure 18.4. Estrogen receptors can also influence gene activity through SP1 and NFKB sites by direct and indirect interactions. Moreover, ERa activity is modulated by protein-protein interactions with Cyclin D1 (^■5.2) and, intriguingly, with BRCA1 (—>18.3). In addition, estrogens - like several

Figure 18.4 Interaction of steroid hormones and EGF-like growth factors in the regulation of estrogen receptor a action

other steroid hormones - elicit very rapid effects at the cell membrane which may not be exerted through their canonical receptors, but through direct activation of ion channels. Most importantly, estrogens act on several different cell types in breast tissue, both epithelial and stromal.

There are two different estrogen receptors in man, estrogen receptor a and estrogen receptor p, which are encoded by two distinct genes, ESR1 and ESR2. They exhibit only 30% homology overall (Figure 18.2), but almost identical DNA-binding domains, both recognizing the 'ERE' sequence AGGTCA NNN TGACCT. ERa mediates most of the proliferative effects in female reproductive tissues. In contrast, ERp appears to act mostly as an inhibitor of ERa action, and perhaps even of the androgen receptor in males. The two estrogen receptors are expressed in different patterns throughout the human body.

Different subunits of the progesterone receptor (PRA and PRB) are translated from differently spliced mRNAs from the same gene. They can bind interchangably as homodimers or heterodimers. Expression of the PR is induced by ERa. PRA (also called PRa), in particular, appears to act as a feedback inhibitor of ERa. However, it is important to realize that PR action is dependent on gestagens, so its actual effect depends on the relative levels of gestagens.

Even more importantly, while estrogen receptors and progesterone receptors are present in many organs of the female (and even male), the effects of estrogens and gestagens are not the same in each tissue. Estrogens affect e.g. the brain and bone, but they do not stimulate proliferation in these tissues as in breast and endometrium.

Even the effects of estrogens on breast and endometrium differ (like those of gestagens). Therefore, since many organs contain receptors, additional mechanisms ensure the tissue specificity of estrogen action. One possible mechanism is differential expression of the two estrogen receptors. A second mechanism is provided by different expression patterns of co-activators, co-repressors and differences in their regulation. As a consequence, certain compounds with structural similarities to estrogens act as partial antagonists that inhibit estrogen activity to a different extent in different organs. These are designated SERMs, for 'selective estrogen receptor modulators'. Tamoxifen and raloxifene are examples of compounds in this class (Figure 18.5). Tamoxifen, e.g., blocks the stimulation of proliferation by estrogens in the breast, acting as an antagonist, but in the endometrium it rather behaves as an agonist, supporting proliferation. This difference may largely be caused by higher levels of the co-activator SRC1 in the endometrium, which is recruited by the tamoxifen-ERa holocomplex. In contrast, in breast tissue, this complex overwhelmingly recruits co-repressors.

Figure 18.5 Structure of estrogens Estrone (or oestrone) and estradiol (oestradiol, E2) are the main estrogens in humans formed from the precursors shown by aromatase and other biosynthetic enzymes. The main pathway of metabolism leading to excretion is initiated by hydroxylation at the 2-position in ring A, marked by an asterisk in estradiol. For comparison, the structure of the (partial) anti-estrogen drug tamoxifen is shown in the lower right corner.

Figure 18.5 Structure of estrogens Estrone (or oestrone) and estradiol (oestradiol, E2) are the main estrogens in humans formed from the precursors shown by aromatase and other biosynthetic enzymes. The main pathway of metabolism leading to excretion is initiated by hydroxylation at the 2-position in ring A, marked by an asterisk in estradiol. For comparison, the structure of the (partial) anti-estrogen drug tamoxifen is shown in the lower right corner.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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