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.

Keywords: Breast cancer; Cancer stem cells; Hormone replacement therapy; Progesterone; Progesterone receptor; Steroid hormone.

Fig. 1

Schematic of described mechanisms involved in steroid hormone regulation of cancer stem cell populations. Estrogens bind estrogen receptor alpha (ER) to increase transcription of target genes FGF9, let-7, and miR-29abc. FGF9 is involved in paracrine, and possibly autocrine, signaling to increase transcription of the transcription factor Tbx3. Estrogens can also bind GPR30 to initiate EGFR and Hippo signaling pathways. Progesterone or progestins bind progesterone receptor (PR) to increase expression of transcription factors (Stat5, Bcl6, Klf5, and Klf4), Notch pathway members (Notch2, Jagged1), and members of the Wnt family (Wnt-1). Wnts and other extrinsic factors may be secreted to influence dedifferentiation of the secreting or neighboring cells. Both progesterone and progestins bind PR to downregulate GATA3, miR-141, or miR-29abc, and increase CSC populations; GATA3 upregulates expression of miR-29b. Androgens or progestins bind androgen receptor (AR) to suppress let-7 microRNA transcription. ER downregulates miR-221/222, which represses translation of ER, miR-29abc blocks translation of Klf4, and miR-141 blocks translation of both Stat5 and PR. Prolactin binds prolactin receptor (PRLR) to block expression of the transcription factor BCL6, which suppresses progestin-dependent induction of CK5