Abstract B006: Tumor cell heterogeneity of prolactin-induced ERα+ mammary carcinomas
Authors: Shea Michael P. , O'Leary Kathleen A. , Schuler Linda A. 
Published: May 2015

Anti-estrogenic therapies have significantly improved the survival of women with estrogen-receptor alpha (ERα) positive breast tumors. Unfortunately 25% of women who suffer from ERα+ cancer experience recurrence of tumors which can exhibit strong therapeutic resistance. The mechanisms underlying the onset of anti-estrogen resistant tumors following treatment are not well understood, but emerging evidence is now implicating tumor-initiating cells (TICs) in tumor growth, treatment resistance, and differentiation. TICs represent a small discrete subpopulation of cells which have the ability to drive the growth of an entire heterogeneous tumor. Elevated circulating prolactin (PRL) levels have been shown to be associated with ERα+ breast tumor incidence, and also correlate with increased metastasis and treatment resistance. To examine the relationship between TICs and treatment resistance in ERα+ mammary carcinomas, we utilized a transgenic mouse model (NRL-PRL), established on a FVB/N background, that mimics the local expression of PRL within the mammary epithelia as observed in women. After a long latency, nulliparous NRL-PRL females develop locally invasive mammary carcinomas, with some observed lung and bone metastases. Importantly, PRL-induced mammary tumors exhibit wide histological diversity and the majority are ERα+ (&gt;75% of tumors). Although development of tumors is accelerated by supplemental estrogen, end stage tumors are insensitive to estrogen, similar to the luminal B subtype. A panel of 20 ERα+ glandular and papillary adenocarcinomas was collected from NRL-PRL females. Their histological appearances and ERα expression were retained after transplantation into mammary glands of wild-type syngeneic recipients. To analyze tumor cell heterogeneity, subpopulations were characterized by subjecting enzymatically dispersed tumor cells to fluorescence-activated cell sorting (FACS). PRL-induced ERα+ tumors consistently displayed high percentages of both luminal (EPCAMhiCD49fmed) and basal (EPCAMloCD49fhi) cells, which is distinct from the luminal but ERα- (MMTV-Her2/neu) and claudin-low (p53-/-) mouse models of breast cancer. The luminal/basal cell ratios for NRL-PRL, MMTV-Her2/neu, and p53-/- derived tumors were 2.4±0.4, 46.0±1.8, and 0.004±0.005, (mean±S.D., N=3-4), respectively. The basal compartment exhibits relatively high TIC enrichment in several well-characterized models of breast cancer. However, recent evidence suggests that the luminal compartment may contain a luminal-progenitor subpopulation which also displays some TIC activity. Interestingly, expression of the surface-marker CD61 in PRL-induced tumors was distributed across both luminal and basal cell compartments. Ongoing limiting-dilution transplantation studies will identify fractions containing TIC activity. Transgenic mammary production of PRL is a useful mouse model to study aggressive ERα+ breast cancer that will provide novel insights into this disease. Supported by R01 CA157675 and T32 ES007015.

Citation Format: Michael P. Shea, Kathleen A. O'Leary, Linda A. Schuler. Tumor cell heterogeneity of prolactin-induced ERα+ mammary carcinomas. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B006.