Mammary stem cells and breast cancer - taking cues from steroid hormones — ASN Events

Mammary stem cells and breast cancer - taking cues from steroid hormones (#1)

Geoffrey J Lindeman 1 2 3 , Marie-Liesse Asselin-Labat 1 2 , François Vaillant 1 2 , Elgene Lim 1 2 , Bhupinder Pal 1 2 , Di Wu 1 2 , Gordon K Smyth 1 2 , Jane E Visvader 1 2
  1. The University of Melbourne, Parkville, VIC, Australia
  2. The Walter & Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  3. The Royal Melbourne Hospital, Parkville, VIC, Australia

The ovarian hormones oestrogen and progesterone profoundly influence breast cancer risk, underscored by the benefit of endocrine therapy in breast cancer . Modulation of their effects through ovarian ablation or chemoprevention also significantly decreases breast cancer incidence. Conversely, there is an increased risk of breast cancer associated wit pregnancy in the short term. The cellular mechanisms underlying these observations, however, are poorly understood.

We have shown that mouse mammary stem cells (MaSCs)1  are highly responsive to steroid hormone signalling, despite lacking the oestrogen and progesterone receptors. Oophorectomy 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. Thus, MaSCs are exquisitely sensitive to hormone signalling, presumably mediated via paracrine signalling. RANK ligand signalling was implicated in this paracrine pathway. These findings suggest a cellular basis for the short-term increase in breast cancer incidence that accompanies pregnancy and further suggest that breast cancer chemoprevention may be achieved, in part, through suppression of MaSC function.2

To gain insights into the cell types in breast tissue that could serve as targets for neoplastic transformation, human basal/stem cell and luminal populations have also been also been isolated. Gene profiling revealed remarkable similarities with certain subtypes of breast cancer. Notably, the luminal progenitor signature (and not the basal/stem cell signature) was most similar to basal-like breast cancer. Moreover, breast tissue from breast cancer prone BRCA1 mutation carriers contained increased of luminal progenitor cells with aberrant growth and differentiation properties. Taken together, these findings suggest that luminal progenitors (and not basal/stem cells) are the likely target that give rise to basal-like breast cancer.3

  1. Shackleton et al, Nature, 2006, 439:84-8
  2. Asselin-Labat et al, Nature, 2010, 465:798-802
  3. Lim et al, Nature Medicine, 2007, 15:907-13