Transcriptional and spatiotemporal regulation of prolactin receptor mRNA and cooperativity with progesterone receptor function during ductal branch growth in the mammary gland.

Molecular and Cellular Endocrinology Section, Center for Cancer Research, NCI, NIH, 10 Center Drive, Bethesda, MD 20892-1402, USA.
Developmental Dynamics (Impact Factor: 2.59). 11/2001; 222(2):192-205. DOI:10.1002/dvdy.1179
Source: PubMed

ABSTRACT Ductal branching within the mammary gland is stimulated by prolactin (PRL) and progesterone (P) acting through their receptors (PRLR and PR). Analysis of mammary gland PRLR expression revealed increasing expression of the long form (L-PRLR) and two of the three short forms (S1- and S3-PRLR) during puberty that became maximal late in pubescence and early gestation, then declined during gestation. By contrast, S2-PRLR mRNA levels remained constant. Examination of stromal PRLR revealed the consistent expression of L-PRLR mRNA. By contrast, S1-PRLR was present only in the mammary fat pad of neonates, whereas high neonatal expression of S2-PRLR became undetectable during puberty. Stromal expression of S3-PRLR decreased to low levels during puberty and was undetectable during lactation and involution. Exogenous PRL stimulated DNA synthesis in both epithelial and adjacent stromal cells in vivo. Distribution of PRLR mRNA in mammary epithelium was homogeneous before puberty and heterogeneous during puberty, gestation, and early lactation. A mutual role for PRLR and PR was suggested wherein PR mRNA increased beyond 6 weeks to maximal levels during puberty and gestation then became undetectable during lactation. In situ hybridization revealed that PR mRNA distribution is homogeneous in the ductal epithelium before 6 weeks and heterogenous during puberty and gestation and that PRLR and PR are similarly distributed in the ductal epithelium. Neither hormone stimulated DNA synthesis in mammary glands of ovariectomized females while their effects interacted markedly. These results demonstrate differential PRLR transcription by epithelial and stromal cells and a similar distribution of PRLR and PR that may facilitate the interaction between P and PRL during ductal branching in the mammary gland.

0 0
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: INTRODUCTION: Puberty is a period of increased susceptibility to factors that cause increased breast cancer risk in adulthood. Mammary end buds (EB) that develop during puberty are believed to be the targets of breast cancer initiation. While the role of estrogen (E) has been extensively studied in pubertal mammary gland development, the role of progesterone (P) during puberty is less defined. METHODS: Pubertal and pre-pubertal ovariectomized mice were treated with vehicle control (C), E, P or E+P. Mammary glands from these mice were analyzed for changes in morphology, proliferation, and expression of the downstream targets amphiregulin (AREG) and Receptor Activator of NF-kB Ligand (RANKL). RESULTS: P, acting specifically through the progesterone receptor, induced increases in mammary gland proliferation and EB formation that were associated with increased AREG expression in ducts and EBs. E, acting specifically through the estrogen receptor, produced similar responses also mediated by AREG. Blocking AREG action by treatment with an epidermal growth factor receptor (EGFR) inhibitor completely abrogated the effect of P on EB formation and proliferation and significantly reduced proliferation within ducts. P also increased expression of RANKL, primarily in ducts. Treatment with RANK-Fc, an inhibitor of RANKL, reduced P-dependent proliferation in ducts and to a lesser extent in EB, but did not cause EB regression. CONCLUSIONS: These results demonstrate a novel P-specific effect through AREG to cause EB formation and proliferation in the developing mammary gland both prior to and during puberty. Thus, hormones and/or factors in addition to E that up-regulate AREG can promote mammary gland development and have the potential to affect breast cancer risk associated with pubertal mammary gland development.
    Breast cancer research: BCR 05/2013; 15(3):R44. · 5.87 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: TP53 is one of the most commonly mutated genes in cancer. In breast cancer, it is mutated in about 40% of primary clinical tumors and is associated with poor survival. The mammotrophic hormone, prolactin (PRL), and/or its receptor are also expressed in many breast cancers, and accumulating epidemiologic data link PRL to breast cancer development and progression. Like TP53 mutations, evidence for PRL activity is evident across several molecular cancer subtypes, and elevated PRL expression and loss of p53 have been observed in some of the same clinical tumors. In order to examine the interaction of these factors, we used genetically modified mouse models of mammary-specific p53 loss and local overexpression of PRL. We demonstrated that mammary PRL decreased the latency of tumors in the absence of p53, and increased the proportion of triple-negative claudin-low carcinomas, which display similarities to human clinical metaplastic carcinomas. Moreover, PRL/p53(-/-) carcinomas displayed higher rates of proliferation and more aggressive behavior. Transcripts associated with cell cycle progression, invasion and stromal reactivity were differentially expressed in carcinomas that developed in the presence of elevated PRL. PRL/p53(-/-) carcinomas also exhibited selectively altered expression of activating protein-1 components, including higher levels of c-Jun and FosL1, which can drive transcription of many of these genes and the epithelial-mesenchymal transition. The ability of PRL to promote claudin-low carcinomas demonstrates that PRL can influence this subset of triple-negative breast cancers, which may have been obscured by the relative infrequency of this cancer subtype. Our findings suggest novel therapeutic approaches, and provide a preclinical model to develop possible agents.Oncogene advance online publication, 22 July 2013; doi:10.1038/onc.2013.278.
    Oncogene 07/2013; · 7.36 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Many organs respond to physiological challenges by changing tissue size or composition. Such changes may originate from tissue-specific stem cells and their supportive environment (niche). The endocrine system is a major effector and conveyor of physiological changes and as such could alter stem cell behavior in various ways. In this review, we examine how hormones affect stem cell biology in four different organs: the ovary, intestine, hematopoietic system, and mammary gland. Hormones control every stage of stem cell life, including establishment, expansion, maintenance, and differentiation. The effects can be cell autonomous or non-cell autonomous through the niche. Moreover, a single hormone can affect different stem cells in different ways or affect the same stem cell differently at various developmental times. The vast complexity and diversity of stem cell responses to hormonal cues allows hormones to coordinate the body's reaction to physiological challenges. Expected final online publication date for the Annual Review of Cell and Developmental Biology Volume 29 is October 06, 2013. Please see for revised estimates.
    Annual Review of Cell and Developmental Biology 07/2013; · 17.98 Impact Factor


Available from
Oct 28, 2013