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Abstract 3273: Prolactin promotes breast lesion progression and alters tumor histotype

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC

Prolactin (PRL) is critical for mammary development and lactation. Epidemiological studies also support a role for PRL in breast cancer (1). In order to study the contributions of PRL to tumor development and progression, we developed a transgenic mouse model that expresses PRL in the mammary epithelial cells (NRL-PRL), mimicking the mammary PRL production in women (2). To explore the interactions of PRL and Wnts in mammary tumorigenesis, NRL-PRL mice were crossed with APCmin/+ mice, which have elevated canonical Wnt signals secondary to reduced β-catenin degradation. Females were administered a single ip dose of ENU (50 mg/kg body weight) at 35-40 days of age. This paradigm in the F1 (FVB/N x C57BL/6J) strain background resulted in few mammary tumors (14%) in NRL-PRL nonparous females. APCmin/+ animals developed tumors at a slightly higher incidence (27%), as previously reported (3). However, penetrance rose to 66% in NRL-PRL/APCmin/+ females, indicating that PRL potentiates APCmin/+-induced tumorigenesis (P=0.008). The presence of PRL also strongly impacted the tumor histotype (P<0.0001). The majority of tumors in APCmin/+ animals were composed of squamous nodules with pilar lesions (63%), while tumors in PRL/ APCmin/+ animals were most often adenocarcinomas of varying histotype (75%). Glands from younger age-matched nonparous females (120 d), prior to palpable lesions, were examined to begin to determine the mechanism of PRL actions. Analyses of “whole mounted” glands showed that both APCmin/+ and PRL/ APCmin/+ animals exhibited multiple epithelial hyperplasias. However, although the numbers of hyperplasias were similar between the two genotypes, the lesions were significantly larger in the PRL/ APCmin/+ glands (P<0.05). This correlated with an increase in the proliferation rate (P<0.01), but no change in apoptosis. Thus, PRL appears to promote tumor progression and affect factors influencing tumor histotype in the APCmin/+ model. The NRL-PRL mouse provides a means of studying how PRL promotes breast cancer alone and in conjunction with other oncogenes.

1Tworoger SS, Hankinson SE. (2008) J Mammary Gland Biol Neoplasia. 13:41-53.

2Arendt LM, Schuler LA. (2008) J Mammary Gland Biol Neoplasia. 13:29-40.

3Moser AR, Hegge LF, Cardiff RD. (2001) Cancer Res. 61: 3480-3485.

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 3273.