DOI 10.1515/hmbci-2013-0007 Horm Mol Biol Clin Invest 2013; 14(2): 57–63
John A. Eden*
Menopausal status, adipose tissue, and breast cancer risk: impact of estrogen replacement therapy Abstract: The seeds of breast cancer are likely sown in the first two or three decades of life. Rapid weight gain and height in infancy predict breast cancer risk in later life. The age at first pregnancy is also a strong predictor for breast cancer; the earlier the first full-term pregnancy, then the lower the risk of breast cancer in later life. It has been postulated that the breast stem cell number may be the factor linking these observations together. Menopause, per se, is associated with an increase in central adiposity, which is reversed by hormone replacement usage. Breast and nonbreast fat both produce estrogens and cytokines that may promote the growth of small breast cancers making them appear earlier. Obesity also is associated with metabolic syndrome, which is a risk factor for breast cancer. The breast cancer stem cells make up only around 1%–2% of the tumor mass and, yet, are the likely driver for much of a breast cancer’s behavior. Future research into breast cancer biology, especially into the cancer stem cells is likely to translate into novel methods of treatment and prevention of this common cancer. Keywords: adipose; breast cancer; breast cancer stem cells; breast development; estrogen; hormone therapy; menopause; progesterone; progestin. *Corresponding author: John A. Eden, Women’s Health and Research Institute of Australia, Level 12, 97–99 Bathurst St, Sydney, 2000, Australia, Phone: +61 1300 722 206, Fax: +61 2 9283 1158, E-mail: [email protected] John A. Eden: Department of Benign Gynaecology, Royal Hospital for Women, Sydney, Australia; and School of Women and Children’s Health, University of NSW, Sydney, Australia
Introduction In the last two decades, there has been much research into the etiology and pathophysiology of breast cancer. The breast cancer risk relates to the reproductive markers such as the age of the first pregnancy, age at menarche and menopause, as well as height, adiposity, and hormone replacement (HRT) usage [1–3]. Currently, there are two main theories of carcinogenesis, which are not necessarily mutually exclusive [4].
The first is the clonal theory, which postulates that genetic and epigenetic modifications to cells (especially tumor suppressor genes) induce changes such as an increased growth rate, angiogenesis and/or other changes in the local microenvironment, which permit the malignantly transformed cell to escape regulatory control and so, permit clonal tumor expansion. The alternate model, the cancer stem cell theory, has arisen in the last decade. It has become clear that both the normal and malignant breast contains stem cells that regulate both the normal and malignant tissue [4–7]. There is abundant evidence that the cancer stem cells play a critical role in breast cancer [5–7]. Typically, the breast cancer stem cells are ER-PR- unlike their offspring, which often acquire hormone receptors. It is the breast cancer stem cell, attempting to make “a breast within the breast,” that produces malignant stromal, fat, and epithelial cells. Once the malignant process is established, other stem cells (fat, stroma, hematopoetic) may be recruited into the tumor. The focus of this series is the impact of adipose tissue on sex-steroid pathophysiology. As will be discussed later, the stroma around the tumor, including the fat, plays a key role in malignant progression. Also, the adipose tissue generally (including distal to the breast) plays an important role affecting the systemic estrogens and cytokines. This review will explore the relationships among menopause, HRT usage, breast fat, as well as adiposity, generally. For this review the University of NSW search engine, Sirius, was used to seek articles in Scopus, using the keywords adipose, fat, hormone therapy, breast cancer, breast cancer stem cells, estrogen, progesterone, progestin, hormone therapy, menopause, breast deve lopment. Preference was given to the human studies and reviews.
Body of review The importance of breast stem cells The pathophysiology of the normal and malignant breast stem cells has been reviewed elsewhere [4–11]. A short overview follows.
58 Eden: Menopause, HRT, fat, and breast cancer risk When the normal differentiated cells undergo mitosis, they divide symmetrically into two similar daughter cells. In contrast, the stem cells, at times, divide symmetrically and, then, at other times, divide asymmetrically into two non-identical cells. One is a clone of the original stem cell and the other, progenitor cell, begins down the path of differentiation. The stem cells may be totipotent and embryonic or somatic and multi-, bi-, or unipotent. The stem cells persist throughout the life of the organism, in contrast to the short-lived somatic differentiated cell. As such, stem cells are much more likely to acquire DNS damage than differentiated cells. The stems are mostly quiescent, very slowly dividing cells. Their main function in normal tissue is to replace the dying cells and repair the tissue damage. Some of the characteristics of the breast stem cells are listed in Table 1. The terminal duct lobular unit (TDLU) is the basic functional breast unit. The duct and terminal alveolar cells are surrounded by myoepithelial tissue. The stem cell niches are located along the breast duct, and within these niches is a hierarchy of cells. The ER- breast stem cell is tightly regulated within its niche. ER+ progenitors usually surround the stem cell, and from these, differentiated duct, alveoli, or stromal cells are produced. The normal breast stem cells are regulated by a large number of growth factors and cytokines.
A short overview of the normal breast from fetal life to puberty Our knowledge of the normal human breast development is remarkably limited [4–7, 11, 12]. Gusterson and Stein [12] point out that there are fewer than 20 publications containing significant information on fetal, infant, and pubertal aspects of human breast development. In contrast, there is an extensive literature available on the mouse breast. In humans, a mammary band can be seen around 5 weeks of gestational age. Around 20 weeks of age, the
epithelial outgrowths can be seen penetrating into the mesenchyme. No ERα is expressed in the human fetal breast tissue until around 30 weeks of gestation, which implies that the breast tissue growth seen up to this time is independent of estrogen (maternal or fetal derived). By birth, a network of breast ducts has formed with an end vesicle containing colostrum. During infancy, the breast growth simply parallels the growth of the rest of the body. As puberty begins, the breast buds form. These alveolar buds cluster around a terminal duct forming the lobule type 1 (lob 1).
Oncogenic influences during fetal life and infancy High birth weight, rapid weight gain during infancy, tall adult height, increased mammary gland mass, and the western diet have all been linked to breast cancer risk in later life [1]. Trichopoulos has suggested that breast stem cell number explains these epidemiological observations [1]. Furthermore, he has suggested that breast cancer risk directly relates to breast stem cell number and that this is determined, at least in part, in fetal life (and infancy). It is likely regulated by the peptide growth factors such as IGF-1. Pregnancy reduces the stem cell number and makes them less vulnerable to malignant change. Thus, the earlier the first pregnancy occurs, the lower the breast cancer risk in later life. The breast stimulating hormones may affect the stem cell number and cause the proliferation of the initiated clones.
Breast development and stem cells, puberty, and the reproductive years Early puberty is characterized by low levels of unopposed estrogen. Ovulation usually begins a couple of years after menarche, and large amounts of estradiol and progesterone are then released cyclically. The breast size increases
Table 1 Some of the characteristics of the breast stem cells. Surface markers elaborated include – epithelial-specific antigen (ESA), CD10, CD44, CD24, ALDH1, Bmi-1, cytokeratins 5/6, 14, and 19, HER2+, EpCAM, p21, Mushashi-1, Sialomucin (Muc) Stems typically form microspheres in cell culture Because of their age, stems are exposed to genotoxic insults for much longer than short-lived somatic cells Critical molecular pathways that regulate stem cell renewal (e.g., NOTCH) are often deregulated in tumors Only stems can form tumors when transplanted into nude mice (often only need 20 cells) Nearly always express CD44+, CD24-/low, Lin- [cell surface markers], and/or ALDH1 [aldehyde dehydrogenase] Breast (cancer) stems are usually, but not always, ER
John A. Eden*
Menopausal status, adipose tissue, and breast cancer risk: impact of estrogen replacement therapy Abstract: The seeds of breast cancer are likely sown in the first two or three decades of life. Rapid weight gain and height in infancy predict breast cancer risk in later life. The age at first pregnancy is also a strong predictor for breast cancer; the earlier the first full-term pregnancy, then the lower the risk of breast cancer in later life. It has been postulated that the breast stem cell number may be the factor linking these observations together. Menopause, per se, is associated with an increase in central adiposity, which is reversed by hormone replacement usage. Breast and nonbreast fat both produce estrogens and cytokines that may promote the growth of small breast cancers making them appear earlier. Obesity also is associated with metabolic syndrome, which is a risk factor for breast cancer. The breast cancer stem cells make up only around 1%–2% of the tumor mass and, yet, are the likely driver for much of a breast cancer’s behavior. Future research into breast cancer biology, especially into the cancer stem cells is likely to translate into novel methods of treatment and prevention of this common cancer. Keywords: adipose; breast cancer; breast cancer stem cells; breast development; estrogen; hormone therapy; menopause; progesterone; progestin. *Corresponding author: John A. Eden, Women’s Health and Research Institute of Australia, Level 12, 97–99 Bathurst St, Sydney, 2000, Australia, Phone: +61 1300 722 206, Fax: +61 2 9283 1158, E-mail: [email protected] John A. Eden: Department of Benign Gynaecology, Royal Hospital for Women, Sydney, Australia; and School of Women and Children’s Health, University of NSW, Sydney, Australia
Introduction In the last two decades, there has been much research into the etiology and pathophysiology of breast cancer. The breast cancer risk relates to the reproductive markers such as the age of the first pregnancy, age at menarche and menopause, as well as height, adiposity, and hormone replacement (HRT) usage [1–3]. Currently, there are two main theories of carcinogenesis, which are not necessarily mutually exclusive [4].
The first is the clonal theory, which postulates that genetic and epigenetic modifications to cells (especially tumor suppressor genes) induce changes such as an increased growth rate, angiogenesis and/or other changes in the local microenvironment, which permit the malignantly transformed cell to escape regulatory control and so, permit clonal tumor expansion. The alternate model, the cancer stem cell theory, has arisen in the last decade. It has become clear that both the normal and malignant breast contains stem cells that regulate both the normal and malignant tissue [4–7]. There is abundant evidence that the cancer stem cells play a critical role in breast cancer [5–7]. Typically, the breast cancer stem cells are ER-PR- unlike their offspring, which often acquire hormone receptors. It is the breast cancer stem cell, attempting to make “a breast within the breast,” that produces malignant stromal, fat, and epithelial cells. Once the malignant process is established, other stem cells (fat, stroma, hematopoetic) may be recruited into the tumor. The focus of this series is the impact of adipose tissue on sex-steroid pathophysiology. As will be discussed later, the stroma around the tumor, including the fat, plays a key role in malignant progression. Also, the adipose tissue generally (including distal to the breast) plays an important role affecting the systemic estrogens and cytokines. This review will explore the relationships among menopause, HRT usage, breast fat, as well as adiposity, generally. For this review the University of NSW search engine, Sirius, was used to seek articles in Scopus, using the keywords adipose, fat, hormone therapy, breast cancer, breast cancer stem cells, estrogen, progesterone, progestin, hormone therapy, menopause, breast deve lopment. Preference was given to the human studies and reviews.
Body of review The importance of breast stem cells The pathophysiology of the normal and malignant breast stem cells has been reviewed elsewhere [4–11]. A short overview follows.
58 Eden: Menopause, HRT, fat, and breast cancer risk When the normal differentiated cells undergo mitosis, they divide symmetrically into two similar daughter cells. In contrast, the stem cells, at times, divide symmetrically and, then, at other times, divide asymmetrically into two non-identical cells. One is a clone of the original stem cell and the other, progenitor cell, begins down the path of differentiation. The stem cells may be totipotent and embryonic or somatic and multi-, bi-, or unipotent. The stem cells persist throughout the life of the organism, in contrast to the short-lived somatic differentiated cell. As such, stem cells are much more likely to acquire DNS damage than differentiated cells. The stems are mostly quiescent, very slowly dividing cells. Their main function in normal tissue is to replace the dying cells and repair the tissue damage. Some of the characteristics of the breast stem cells are listed in Table 1. The terminal duct lobular unit (TDLU) is the basic functional breast unit. The duct and terminal alveolar cells are surrounded by myoepithelial tissue. The stem cell niches are located along the breast duct, and within these niches is a hierarchy of cells. The ER- breast stem cell is tightly regulated within its niche. ER+ progenitors usually surround the stem cell, and from these, differentiated duct, alveoli, or stromal cells are produced. The normal breast stem cells are regulated by a large number of growth factors and cytokines.
A short overview of the normal breast from fetal life to puberty Our knowledge of the normal human breast development is remarkably limited [4–7, 11, 12]. Gusterson and Stein [12] point out that there are fewer than 20 publications containing significant information on fetal, infant, and pubertal aspects of human breast development. In contrast, there is an extensive literature available on the mouse breast. In humans, a mammary band can be seen around 5 weeks of gestational age. Around 20 weeks of age, the
epithelial outgrowths can be seen penetrating into the mesenchyme. No ERα is expressed in the human fetal breast tissue until around 30 weeks of gestation, which implies that the breast tissue growth seen up to this time is independent of estrogen (maternal or fetal derived). By birth, a network of breast ducts has formed with an end vesicle containing colostrum. During infancy, the breast growth simply parallels the growth of the rest of the body. As puberty begins, the breast buds form. These alveolar buds cluster around a terminal duct forming the lobule type 1 (lob 1).
Oncogenic influences during fetal life and infancy High birth weight, rapid weight gain during infancy, tall adult height, increased mammary gland mass, and the western diet have all been linked to breast cancer risk in later life [1]. Trichopoulos has suggested that breast stem cell number explains these epidemiological observations [1]. Furthermore, he has suggested that breast cancer risk directly relates to breast stem cell number and that this is determined, at least in part, in fetal life (and infancy). It is likely regulated by the peptide growth factors such as IGF-1. Pregnancy reduces the stem cell number and makes them less vulnerable to malignant change. Thus, the earlier the first pregnancy occurs, the lower the breast cancer risk in later life. The breast stimulating hormones may affect the stem cell number and cause the proliferation of the initiated clones.
Breast development and stem cells, puberty, and the reproductive years Early puberty is characterized by low levels of unopposed estrogen. Ovulation usually begins a couple of years after menarche, and large amounts of estradiol and progesterone are then released cyclically. The breast size increases
Table 1 Some of the characteristics of the breast stem cells. Surface markers elaborated include – epithelial-specific antigen (ESA), CD10, CD44, CD24, ALDH1, Bmi-1, cytokeratins 5/6, 14, and 19, HER2+, EpCAM, p21, Mushashi-1, Sialomucin (Muc) Stems typically form microspheres in cell culture Because of their age, stems are exposed to genotoxic insults for much longer than short-lived somatic cells Critical molecular pathways that regulate stem cell renewal (e.g., NOTCH) are often deregulated in tumors Only stems can form tumors when transplanted into nude mice (often only need 20 cells) Nearly always express CD44+, CD24-/low, Lin- [cell surface markers], and/or ALDH1 [aldehyde dehydrogenase] Breast (cancer) stems are usually, but not always, ER
