Abstract 4220: Identification of novel developmental and differentiation markers in the breast
Authors: Wood Charles E. , Stute Petra , Dillon Sara , O'Donnell Russell , Register Thomas , Cline Mark 
Published: February 2011

Background: The majority of cell growth pathways implicated in breast cancer have dual physiologic roles in normal mammary gland development. Similarly, founder stem cells in breast cancer may share important phenotypic characteristics with progenitor cells in early mammary gland development. The goal of this project was to investigate transcriptional profiles in the early pubertal primate mammary gland in order to identify novel markers and pathways involved in development, differentiation, and potentially breast cancer risk.

Materials and Methods: Mammary gland biopsies from 31 female cynomolgus macaque monkeys were evaluated. Animals ranged in age from 1.5 to 21.8 years. Reproductive stage was determined based on ovarian hormones and breast histology as developmental (pre/peripubertal, n=8) or adult (premenopausal, n=7; pregnant, n=6; lactating, n=5; and postmenopausal, n=5). Transcriptional profiles were generated using Affymetrix cDNA rhesus macaque gene microarrays and analyzed using Genesifter software. All statistical comparisons were adjusted for multiple comparisons.

Results: Predetermined developmental stem cell markers included CD44, CD29, CD24, OSF-2, and ALDH1; no significant changes were noted between developmental and adult profiles for any of these markers at a fold-change &gt;2. Marked upregulation of estrogen receptor alpha (ESR1) and several markers of ESR1 activity were highly upregulated in the developing breast samples (e.g. PGR at 22-fold, TFF1 at 108-fold, and IGFBP1 at 54-fold) (adjusted P&lt;0.0001 for all), while genes markedly upregulated in all adult samples included markers of lipid metabolism / milk production (e.g. lactalbumin at 33-fold, casein alpha s1 at 29-fold) and immunoglobulin production (e.g. IGHG1 at 36-fold, IGHM at 33-fold) (adjusted P&lt;0.0001 for all). Novel markers highly upregulated in the developing breast included POSTN at 22-fold, KLK11 at 34-fold, KLK12 at 18-fold, PENK at 22-fold, IL13RA2 at 14-fold, CST1 at 13-fold, and NEK10 at 15-fold (adjusted P&lt;0.0001 for all). Pathways significantly overrepresented (z-score &gt; 2) among genes increased in developmental samples included extracellular matrix remodeling, focal adhesion, cytokine receptor interactions, and transforming growth factor-beta signaling.

Discussion: Mammary morphogenesis during puberty is characterized by dramatic bursts of proliferation, differentiation, migration, and remodeling orchestrated by a complex but poorly understood network of molecular signals, many of which may also have more ominous dual roles in breast carcinogenesis. In this study we identify a novel group of markers that are highly expressed during this critical window of development. These findings should prove useful in the future study of breast cancer progenitor / stem cells and the role of aberrant developmental signals in early breast carcinogenesis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4220.