Steroid Hormones, Steroid Receptors, and Breast Cancer Stem Cells

Abstract

The ovarian hormones progesterone and estrogen play important roles in breast cancer etiology, proliferation, and treatment. Androgens may also contribute to breast cancer risk and progression. In recent years, significant advances have been made in defining the roles of these steroid hormones in stem cell homeostasis in the breast. Stem cells are potential origins of breast cancer and may dictate tumor phenotype. At least a portion of breast cancers are proposed to be driven by cancer stem cells (CSCs), cells that mimic the self-renewing and repopulating properties of normal stem cells, and can confer drug resistance. Progesterone has been identified as the critical hormone regulating normal murine mammary stem cell (MaSC) populations and normal human breast stem cells. Synthetic progestins increase human breast cancer risk; one theory speculates that this occurs through increased stem cells. Progesterone treatment also increases breast CSCs in established breast cancer cell lines. This is mediated in part through progesterone regulation of transcription factors, signal transduction pathways, and microRNAs. There is also emerging evidence that estrogens and androgens can regulate breast CSC numbers. The evolving concept that a breast CSC phenotype is dynamic and can be influenced by cell signaling and external cues emphasizes that steroid hormones could be crucial players in controlling CSC number and function. Here we review recent studies on steroid hormone regulation of breast CSCs, and discuss mechanisms by which this occurs.

Breast Cancer Suppression by Progesterone Receptors Is Mediated by Their Modulation of Estrogen Receptors and RNA Polymerase III

“…Second, recent genome-wide studies describing that liganded PR impinges on ER mitogenic chromatin interactions, leading to a growth inhibitory phenotype (21, 22). However, the antithesis to these notions are longstanding observations that P4 and progestins exert autonomous proliferative effects in breast cancers under some contexts (reviewed in 3), and more recent discoveries that P4 expands cancer stem cells (reviewed in (5)). Progestin-mediated proliferation tends to occur when progestins are acting in the absence of estrogens, and is especially notable in 3D models (8–10).…”

“…However, PR itself exerts a wide array of autonomous activity in breast cancer cells including liganded and unliganded transcriptional activity, rapid activation through kinases, metabolic alterations, and increased cancer stem cell activity (reviewed in 2, 3–5). PR exerts paradoxical effects on breast cancer growth depending on the experimental conditions.…”

Long non-coding RNAs and genes contributing to the generation of cancer stem cells in hepatocellular carcinoma identified by RNA sequencing analysis

“…The pathways of ʻsubstance metabolism and transport', including ʻsteroid metabolic process' and ʻcholesterol metabolic process' were found to be enriched in the two lists of DEGs. As steroid is an important metabolite, the dysregulation of its functions is associated with the generation of CSCs in many types of cancers and could affect progression (34)(35)(36). In this study, MVD, which is related to cholesterol biosynthesis, was found to be present in both of these two pathways: ʻsteroid biosynthetic/metabolic process' and ʻterpenoid backbone biosynthesis' in the Huh7-C sample.…”

Sex and Sex Hormones in Tissue Homeostasis

“…Many organs contain stem cell niches hosting adult tissue stem cells that are precursor cells maintained in a relatively undifferentiated state ready to replace lost cells by proliferation followed by differentiation [18,19]. [20][21][22][23][24]. Besides these effects, sex hormones were also found to have pronounced effects on the proliferation of different stem cell populations.…”