Control of mammary stem cell function by steroid hormone signalling

Abstract

The ovarian hormones oestrogen and progesterone profoundly influence breast cancer risk, underpinning the benefit of endocrine therapies in the treatment of breast cancer. Modulation of their effects through ovarian ablation or chemoprevention strategies also significantly decreases breast cancer incidence. Conversely, there is an increased risk of breast cancer associated with pregnancy in the short term. The cellular mechanisms underlying these observations, however, are poorly defined. Here we demonstrate that mouse mammary stem cells (MaSCs) are highly responsive to steroid hormone signalling, despite lacking the oestrogen and progesterone receptors. Ovariectomy markedly diminished MaSC number and outgrowth potential in vivo, whereas MaSC activity increased in mice treated with oestrogen plus progesterone. Notably, even three weeks of treatment with the aromatase inhibitor letrozole was sufficient to reduce the MaSC pool. In contrast, pregnancy led to a transient 11-fold increase in MaSC numbers, probably mediated through paracrine signalling from RANK ligand. The augmented MaSC pool indicates a cellular basis for the short-term increase in breast cancer incidence that accompanies pregnancy. These findings further indicate that breast cancer chemoprevention may be achieved, in part, through suppression of MaSC function.

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…However, these MaSCs show a receptor-negative phenotype for ERα, PR, and erbB2 [108]. Despite the lack of steroid hormone receptors, ovariectomy of mice significantly reduced MaSC number and tumor-forming potential in vivo, whereas MaSC recapitulating activity increased in mice treated with E2 plus progesterone [109]. These data indicate an increased risk of breast cancer associated with pregnancy.…”

Progesterone signalling in breast cancer: a neglected hormone coming into the limelight

“…Genetic evidence has been provided that RANKL is required for progesterone-induced proliferation of hormone receptor (HR) -cells and cyclin D1 is required for cell proliferation of HR + cells (bold grey arrows). RANKL has been implicated in the regulation of bipotential stem cells 75,76 and shown to be required for side branching 35 . In Wnt4 -/− and Id4 −/− (REF.…”

“…Instead, they give rise to cystic structures 58 . Both oestrogens and progesterone were implicated in mammary stem cell activation on the basis of an increase in the number of integrin α6 + cells after hormone stimulation of ovariectomized mice 75,76 . RANKL was implicated in this hormone-induced stem cell expansion on the basis of the decreased in vitro clonogenic capacity of integrin β1 + CD24 + cells harvested from mammary glands after in vivo treatment with an antibody against RANKL 76 .…”

“…Both oestrogens and progesterone were implicated in mammary stem cell activation on the basis of an increase in the number of integrin α6 + cells after hormone stimulation of ovariectomized mice 75,76 . RANKL was implicated in this hormone-induced stem cell expansion on the basis of the decreased in vitro clonogenic capacity of integrin β1 + CD24 + cells harvested from mammary glands after in vivo treatment with an antibody against RANKL 76 . Furthermore, genetic ablation of the RANKL receptor RANK abrogated a twofold increase in the integrin α6 + compartment induced by progestin treatment 77 , suggesting that RANKL may activate the stem cells as a paracrine factor.…”

Paracrine WNT5A signaling in healthy and neoplastic mammary tissue

“…1,2 Follow-up studies from the same laboratories further found that progesterone promotes self-renewal of mammary stem cells via paracrine signal transduction, by promoting the PR-mediated expression of Wingless (Wnt) ligands and receptor activator for nuclear factor k-B ligand (Rankl, official name Tumor Necrosis Factor Superfamily, Member 11, TNFSF11). 3,4 Another laboratory confirmed the requirement for Wnt4, but not Rankl, in the progesterone-mediated regeneration capacity of the mammary epithelium. 5 Rankl, on the other hand, is induced by progesterone during pregnancy and leads to the subsequent expansion and differentiation of mammary stem cells into alveolar epithelial cells.…”