Abstract LB-190: Growth hormone signaling in mammary stem and progenitor cells

Abstract

Abstract The role of growth hormone (GH) in development of the normal mammary gland has been convincingly demonstrated in studies that show dramatically impaired mammary development in spontaneous dwarf rats and growth hormone receptor knock-out (GHR-KO) mice. There is also evidence that GH signaling may have a role in breast cancer. Animals treated with GH develop hyperproliferative lesions in the mammary gland and have increased incidence of spontaneous mammary tumors. Conversely, animals deficient in GH signaling are resistant to carcinogen-induced cancers, including mammary carcinoma. In humans, there is an increased incidence of cancer in patients with acromegaly (syndrome caused by excess GH production by pituitary gland) and a decreased incidence in patients with Laron syndrome (GH deficiency). In this study, we show that GH may increase the risk of breast cancer by stimulating stem and progenitor cells to enter the cell cycle. Using immunohistochemistry and immunostaining coupled with flow cytometry analysis, we found that GHR is expressed in stem and progenitor cells in the normal breast epithelium. We have previously shown that cells with ALDH activity from the human mammary epithelium have functional properties of stem/progenitor cells. Two thirds of these ALDH positive cells express GHR. GHR positive mammary epithelial cells are capable to initiate mammosphere formation in suspension culture and can generate both luminal and myoepithelial cell lineages in vitro. GH treatment increased mammosphere formation in a dose dependent manner. Although the total number of progeny was increased in these conditions, cell dynamics analysis using PKH26 dye dilution showed that the ratios between stem cells, early and late progenitor cells were not changed. GH treatment reduced the number of cells in quiescent state (G0) and decreased p21 protein levels, a cell-cycle regulator previously associated with stem cells quiescence. Taken together, these results indicated that GH treatment did not change symmetry of self-renewal cell divisions but increased the number of cycling mammary stem/progenitor cells. We found that GH is present in normal human mammary epithelial cells both in vitro and in vivo. In vitro, GH is secreted by mammary epithelial cells upon progesterone stimulation. We propose a model in which GH, estrogen and progesterone establish a paracrine signaling loop that stimulates GHR positive/steroid receptor negative stem and progenitor cells to enter the cell cycle. We propose that increased levels or prolonged exposure steroid hormones and/or GH would lead eventually to an expanded undifferentiated population at higher risk for transformation through oncogenic hits. Consistent with this concept, analysis of 180 cases of clinical precursor lesions (DCIS) showed an expanded GHR+ cell population in 92% of cases, with expression in 50-100% of the cell population in more than half of cases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-190. doi:1538-7445.AM2012-LB-190