Stem Cells, Hormones, and Mammary Cancer

Abstract

Pregnancy and breast cancerThe incidence of breast cancer is influenced by age, genetics, ethnicity, diet, socioeconomic status, and reproductive history. The latter is the strongest and most reliable risk factor besides age and genetic susceptibility [1]. Reproductive factors have been associated with risk for breast cancer since the 17 th century, when the disease was noted to be more prevalent among Catholic nuns. It is now a well-established fact that a full-term pregnancy early in life is associated with a long-term risk reduction for developing breast cancer. A woman who has her first child after the age of 35 has approximately twice the risk of developing breast cancer as a woman who has a child before age 20 (see current NCI Cancer Fact Sheet on Pregnancy and Breast Cancer Risk). Despite this long-term reduction in breast cancer risk in parous women, epidemiologists agreed at a recent NCI-sponsored workshop on "Early Reproductive Events and Breast Cancer" (http://nci.nih.gov/cancerinfo/ere) that each gestation increases temporarily the likelihood for developing breast cancer [2]. This transient increase in breast cancer risk lasts for a few years after a full-term pregnancy.Pregnancy has a very similar dual effect on the etiology of mammary cancer in animal models. Like humans, parous rats and mice have a greatly reduced susceptibility to chemically induced mammary tumorigenesis compared to their nulliparous siblings [3]. Humans who carry germ line mutations in tumor susceptibility genes do not benefit from the protective effects of pregnancy, but have a significantly greater risk of developing the disease following one or multiple gestation cycles [4]. There are, however, conflicting reports whether lactation influences the onset of breast cancer in women with BRCA1 mutations. The current view on breast cancer as a stem cell disease is founded on compelling evidence that many breast cancers may arise as clonal expansions from epithelial progenitors with an infinite lifespan [5]. It has been hypothesized that unique properties of mammary stem cells, such as self-renewal, make this population a prime target for transformation and tumorigenesis. Several experimental breast cancer models support this hypothesis. The most venerable is the mammary tumor virus [6] model in mice, where MMTV proviral insertions produce mutated mammary cells, which attain immortality (escape from growth senescence) and produce clones of mammary cells with increased propensity to develop mammary cancer. Serial transplantations of these preneoplastic lesions result in the formation of hyperplastic/dysplastic ductal trees, suggesting that multipotent cells are affected by MMTV transformation and that they pass on their neoplastic properties to their descendants [7]. Morphologically undifferentiated cells,

Preponderance of cells with stem cell characteristics in metastasising mouse mammary tumours induced by deregulated EphB4 and ephrin-B2 expression

“…Sca-1 expression is thought to define estrogen receptor (ER)-positive luminal epithelial cells. Although the main portion of this cell population is non-dividing and thus probably end-differentiated, dividing luminal restricted ERpositive progenitor cells are frequently found during puberty and are also present in adulthood (41). Moreover, Booth et al documented the presence of ER-positive cells in the adult mouse mammary gland exhibiting asymmetric cell division, a hall-mark of stem cells (42).…”

Stem Cells of the Breast and Cancer Therapy

“…CSCs can be derived directly from mutational events in Breast cancer is the most common cancer among women in Western Europe and North America, and its prevalence is increasing in developing countries [1]. A number of risk factors are known, among them age, genetic susceptibility, ethnicity, diet, socioeconomic status and reproductive history [2,3]. Among the dietary risk factors, only alcohol intake has a consistent and strong positive association; being overweight constitutes an additional risk [4].…”