Prolactin Regulates Mammary Epithelial Cell Proliferation Via Autocrine/Paracrine Mechanism

Abstract

Prolactin (PRL) is essential for a number of developmental events in the mammary gland. Work with PRL and PRL receptor knockout mice has shown that PRL indirectly regulates ductal side branching during puberty and directly controls lobuloalveolar development and lactogenesis during pregnancy. Anterior pituitary or placental PRL is thought to be responsible for these functions via an endocrine mechanism; however, PRL is also produced in a number of extrapituitary sites including the mammary gland. The physiologic relevance of mammary PRL remains unknown. In this study we utilized mammary recombination in Rag1(-/-) hosts, to determine whether mammary PRL plays a role in the regulation of mammary gland development. Mammary glands formed with the PRL gene deleted from either the epithelium, stroma, or both displayed normal development, on the basis of whole mount and hematoxylin and eosin histology, during puberty and lactation. At the end of pregnancy, a 2.8-fold decrease in bromodeoxyuridine incorporation was observed in the epithelial cells of mammary glands formed using PRL knockout epithelium compared with those formed using wildtype epithelium. No balancing alteration in the rates of apoptosis was detected. Thus, mammary-derived PRL influences mammary epithelial cell proliferation via an autocrine/paracrine mechanism, establishing a physiologic function for mammary PRL during mammopoiesis.

Role of extracellular matrix and prolactin in functional differentiation of bovine BME-UV1 mammary epithelial cells

“…4a). Our observations are consistent with the results of other groups working on the 3D culture system of MECs, which showed that the initiation of alveoli-like morphology formation was primarily driven by the ECM, and the acinar structures were formed even in the absence of PRL (Naylor et al 2003, Riley et al 2010). However, Riley and coworkers (2010) have noted in their microarray study of the transcriptional profile of primary bovine MECs cultured on Matrigel, that PRL is necessary for the high expression levels of milk protein genes.…”

Human prolactin receptors are insensitive to mouse prolactin: implications for xenotransplant modeling of human breast cancer in mice

“…For instance, several laboratories are pursuing the use of human prolactin receptor antagonists in breast cancer treatment (Chen et al 2002, Bernichtein et al 2003. Such antagonists will have distinctly reduced effect in the absence of circulating agonist, even if some tumors produce human prolactin as an autocrine factor (Reynolds et al 1997, Ben-Jonathan et al 2002, Naylor et al 2003. Likewise, drugs targeting prolactin receptor-modulated signaling pathways are expected to have diminished efficacy when tested on human breast cancer in mice.…”

New concepts in prolactin biology

“…non-pathological) conditions remains very limited. For example, local PRL was proposed to play a role in i) mammopoiesis, based on experiments using PRL-deficient mice (Naylor et al 2003), ii) nociception, based on experiments using rat trigeminal sensory neurons (Diogenes et al 2006), or iii) dermatological bioregulation, based on experiments using organ-cultured human hair follicles (Foitzik et al 2009, Ramot et al 2010. Even if these examples are not aimed at being exhaustive, the paucity of knowledge of local PRL contrasts with the pleiotropic actions usually linked to the endocrine hormone (Bole-Feysot et al 1998).…”

“…All these studies pointed to the proliferative/anti-apoptotic role of autocrine/paracrine PRL. As mentioned, due to the rareness of extrapituitary PRL expression in rodents, knockout strategies were rarely used to address functional issues (Naylor et al 2003). Actually, animal models generated to date all involved the opposite strategy, i.e.…”