Loss of mammary epithelial prolactin receptor delays tumor formation by reducing cell proliferation in low-grade preinvasive lesions

Oakes, Samantha; Robertson, Fiona G.; Kench, James G.; Gardiner-Garden, Margaret; Wand, M. P.; Green, J E; Ormandy, Christopher J.

doi:10.1038/sj.onc.1209838

Cited by 71 publications

(60 citation statements)

References 50 publications

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“…The evidence supporting a role for PRL-PRLR signaling in breast cancer is multifold. Directed expression of PRL in the mammary gland in mice induces a high frequency of mammary tumor development (12), whereas genetic knockout of the PRLR loci inhibits the growth of mammary tumors (13). In humans, PRLR protein and/or mRNA have been detected in the majority of breast tumors examined (7) and is overexpressed in malignant epithelium when compared with matched normal breast epithelium (14).…”

Section: Role Of Prl In Breast and Prostate Cancermentioning

confidence: 99%

Molecular Pathways: Blockade of the PRLR Signaling Pathway as a Novel Antihormonal Approach for the Treatment of Breast and Prostate Cancer

Damiano

Wasserman

2013

Clinical Cancer Research

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The prolactin (PRL)-prolactin receptor (PRLR) signaling complex has been implicated in the pathology of breast and prostate carcinoma. A multitude of pro-oncogenic intracellular signaling pathways are activated by PRL in breast and prostate epithelial cells, leading to enhanced cellular proliferation, survival, and tumorigenesis in numerous model systems. Emerging evidence suggests that targeting the PRL-PRLR axis in human cancer may represent an unexploited avenue for therapeutic intervention and, given the extensive cross-talk between PRLR and other signal transduction pathways, a potential means through which other anticancer agents could be rendered more efficacious in the clinic. LFA102 is a potent anti-PRLR neutralizing antibody that efficiently abrogates the function of this receptor in vivo, mediating significant antitumor effects in preclinical models. The clean safety profile of this antibody in animals and in the clinical experiences to date suggests that blocking the PRLR signaling pathway in human tumors may have few significant toxicologic consequences and may be a promising approach to treating cancer. A phase I trial in patients with breast and prostate cancer is underway to better understand the clinical utility of LFA102 and the contribution of PRL to the maintenance and progression of human cancer.

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Section: Role Of Prl In Breast and Prostate Cancermentioning

confidence: 99%

Molecular Pathways: Blockade of the PRLR Signaling Pathway as a Novel Antihormonal Approach for the Treatment of Breast and Prostate Cancer

Damiano

Wasserman

2013

Clinical Cancer Research

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“…In another mouse breast cancer model system, Stat5a-null females exhibited delayed transforming growth factor-a-induced tumorigenesis (Humphreys & Hennighausen 2000). Third, a recent study by Oakes et al (2007) suggested that PRL receptor deficiency may prevent early progression of mammary gland neoplasia to invasive carcinoma. However, it is unclear so far whether this inhibition of mammary gland cancer progression would be due to the lack of JAK2/STAT5 signaling or inhibition of other PRL receptor-activated signal transduction pathways.…”

Section: Stat5a/b In Tumorigenesis Of Rodent Mammary Glandmentioning

confidence: 99%

Signal transducer and activator of transcription 5A/B in prostate and breast cancers

Tan

Nevalainen

2008

Endocrine Related Cancer

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Protein kinase signaling pathways, such as Janus kinase 2-Signal transducer and activator of transcription 5A/B (JAK2-STAT5A/B), are of significant interest in the search for new therapeutic strategies in both breast and prostate cancers. In prostate cancer, the components of the JAK2-STAT5A/B signaling pathway provide molecular targets for small-molecule inhibition of survival and growth signals of the cells. At the same time, new evidence suggests that the STAT5A/B signaling pathway is involved in the transition of organ-confined prostate cancer to hormonerefractory disease. This implies that the active JAK2-STAT5A/B signaling pathway potentially provides the means for pharmacological intervention of clinical prostate cancer progression. In addition, active STAT5A/B may serve as a prognostic marker for identification of those primary prostate cancers that are likely to progress to aggressive disease. In breast cancer, the role of STAT5A/B is more complex. STAT5A/B may have a dual role in the regulation of malignant mammary epithelium. Data accumulated from mouse models of breast cancer suggest that in early stages of breast cancer STAT5A/B may promote malignant transformation and enhance growth of the tumor. This is in contrast to established breast cancer, where STAT5A/B may mediate the critical cues for maintaining the differentiation of mammary epithelium. In addition, present data suggest that activation of STAT5A/B in breast cancer predicts favorable clinical outcome. The dual nature of STAT5A/B action in breast cancer makes the therapeutic use of STAT5 A/B more complex.

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“…In mice, transgenic over-expression of PRL induced formation of mammary tumours (Wennbo et al 1997), many of which were oestrogen receptor (ER)-positive (Rose-Hellekant et al 2003). PRLR knockout studies have shown a decrease of the mammary tumour growth rate (Oakes et al 2007). Based on the in vivo data, PRL was suggested to be a growth factor for cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Prolactin and oestrogen synergistically regulate gene expression and proliferation of breast cancer cells

Rasmussen¹,

Frederiksen²,

Din³

et al. 2010

Endocrine-Related Cancer

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The pituitary hormone prolactin (PRL) plays an important role in mammary gland development. It was also suggested to contribute to breast cancer progression. In vivo data strongly supported a crucial role of PRL in promoting tumour growth; however, PRL demonstrated only a weak, if any, pro-proliferative effect on cancer cells in vitro. Several recent studies indicated that PRL action in vivo may be influenced by the hormonal milieu, e.g. other growth factors such as 17b-oestradiol (E 2 ). Here, we explored the potential interplay between PRL and E 2 in regulation of gene expression and cell growth. PRL alone induced either a weak or no proliferative response of T47D and BT-483 cells respectively, while it drastically enhanced cell proliferation in E 2 -stimulated cultures. Affymetrix microarray analysis revealed 12 genes to be regulated by E 2 , while 57 genes were regulated by PRL in T47D cells. Most of the PRL-regulated genes (42/57) were not previously described as PRL target genes, e.g. WT1 and IER3. One hundred and five genes were found to be regulated upon PRL/E 2 co-treatment: highest up-regulation was found for EGR3, RUNX2, EGR1, MAFF, GLIPR1, IER3, SOCS3, WT1 and AREG. PRL and E 2 synergised to regulate EGR3, while multiple genes were regulated additively. These data show a novel interplay between PRL and E 2 to modulate gene regulation in breast cancer cells.

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Loss of mammary epithelial prolactin receptor delays tumor formation by reducing cell proliferation in low-grade preinvasive lesions

Cited by 71 publications

References 50 publications

Molecular Pathways: Blockade of the PRLR Signaling Pathway as a Novel Antihormonal Approach for the Treatment of Breast and Prostate Cancer

Molecular Pathways: Blockade of the PRLR Signaling Pathway as a Novel Antihormonal Approach for the Treatment of Breast and Prostate Cancer

Signal transducer and activator of transcription 5A/B in prostate and breast cancers

Prolactin and oestrogen synergistically regulate gene expression and proliferation of breast cancer cells

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