The human intermediate prolactin receptor is a mammary proto-oncogene

Grible, Jacqueline M; Zot, Patricija; Olex, Amy L.; Hedrick, Shannon E.; Harrell, J. Chuck; Woock, Alicia E.; Idowu, Michael O.; Clevenger, Charles V.

doi:10.1038/s41523-021-00243-7

Cited by 20 publications

(34 citation statements)

References 48 publications

(49 reference statements)

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“…The participation of the ERα-c/EBP-Sp1 complex at the human PIII promoter region stimulates PRLR transcription/expression independently of estradiol [ 26 , 31 ]. In addition to the role of the predominant long form of PRLR in breast cancer, recently it has been shown that the human intermediate PRLR (alternatively spliced isoform) is a mammary proto-oncogene capable of stimulating cell survival and proliferation [ 40 ]. The oncogenic effect of intermediate PRLR isoform reaches to its full potential when expressed in concert with PRLR long form in MCF-10A cell lines.…”

Section: Prlr Signaling Pathwaymentioning

confidence: 99%

“…Heterodimers of long and intermediate PRLR isoforms displayed greater stability than PRLR long form homodimers. These can activate JAK2/RAS/MAPK pathway, but unable to induce STAT5A phosphorylation [ 40 ].…”

Section: Prlr Signaling Pathwaymentioning

confidence: 99%

“…These can activate JAK2/RAS/MAPK pathway, but unable to induce STAT5A phosphorylation [40]. The most important transcription factor in PRLR signaling is STAT which regulates the growth, differentiation, and survival of mammary tissue.…”

Section: Prlr Signaling Pathwaymentioning

confidence: 99%

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Crosstalk between PRLR and EGFR/HER2 Signaling Pathways in Breast Cancer

Kavarthapu

Anbazhagan

Dufau

2021

Cancers

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Prolactin receptor (PRLR) and epidermal growth factor receptor (EGFR/ERBB) signaling pathways activated by prolactin (PRL) and epidermal growth factor (EGF), have a major role in the mammary gland development and in the etiology of breast cancer, respectively. ER+ breast tumors comprise up to 75% of all breast cancers and 10% of these are HER2+. Elevated levels of PRLR in breast tumors, high circulating levels of PRL and increased expression of ERBB1/2 in patients that become resistant to endocrine therapy have shown to be associated with higher risk of cancer progression. In this review, we examine the role of crosstalk between PRLR and ERBB1/2 signaling pathways in the activation of unliganded ERα, cyclin-D1 and other oncogenic factors (MYC, FOS, JUN) in breast cancer. PRL/PRLR and EGF/EGFR induces phosphorylation of ERα through activation of MEK/MAPK and PI3K/AKT signaling pathways. PRL in breast cancer cells via PRLR/JAK2 can also induce phosphorylation of ERBB2/HER2, which in turn activates the downstream RAS/MEK/ERK pathway required for ERα phosphorylation. EGFR, independent of PRL/PRLR, can activate STAT5 indirectly via c-SRC and drive the expression of target genes involved in cell proliferation and survival. The crosstalk between PRLR and HER2, where PRL induces HER2 signaling can be an alternative route for ERα activation to induce transcription of PRLR and other ER target genes. We believe that overexpression of EGFR/HER2 and PRLR in breast tumors could maximize the actions of their ligands, and further induce cell proliferation promoting malignancy. This could also explain the resistance to endocrine therapy resulting in tumor growth.

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Section: Prlr Signaling Pathwaymentioning

confidence: 99%

Section: Prlr Signaling Pathwaymentioning

confidence: 99%

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Crosstalk between PRLR and EGFR/HER2 Signaling Pathways in Breast Cancer

Kavarthapu

Anbazhagan

Dufau

2021

Cancers

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“…Assessments should consider interactions of PRL with other factors that affect BC such as estrogen and progesterone, the effects of PRL variants, and the relative expression of different PRLR isoforms. Notably, it has been recently reported that the intermediate isoform of the PRLR, which can hetero-dimerize with the long isoform, acts as a proto-oncogene in breast cancer [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Suppression of Breast Cancer by Small Molecules That Block the Prolactin Receptor

Borcherding

Hugo

Fox

et al. 2021

Cancers

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Prolactin (PRL) is a protein hormone which in humans is secreted by pituitary lactotrophs as well as by many normal and malignant non-pituitary sites. Many lines of evidence demonstrate that both circulating and locally produced PRL increase breast cancer (BC) growth and metastases and confer chemoresistance. Our objective was to identify and then characterize small molecules that block the tumorigenic actions of PRL in BC. We employed three cell-based assays in high throughput screening (HTS) of 51,000 small molecules and identified two small molecule inhibitors (SMIs), named SMI-1 and SMI-6. Both compounds bound to the extracellular domain (ECD) of the PRL receptor (PRLR) at 1–3 micromolar affinity and abrogated PRL-induced breast cancer cell (BCC) invasion and malignant lymphocyte proliferation. SMI-6 effectively reduced the viability of multiple BCC types, had much lower activity against various non-malignant cells, displayed high selectivity, and showed no apparent in vitro or in vivo toxicity. In athymic nude mice, SMI-6 rapidly and dramatically suppressed the growth of PRL-expressing BC xenografts. This report represents a pre-clinical phase of developing novel anti-cancer agents with the potential to become effective therapeutics in breast cancer patients.

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“…It was shown that secretion of prolactin also occurs outside the pituitary gland, namely by the endometrium, lymphocytes, decidual membrane, breast, and prostate. In these organs, PRL has cytokine-like properties, binds to PRL-R on the cell surface and cytoplasm, and activates the signaling pathways Jak2/Stat5 and Map Kinase [4,5].…”

Section: Introductionmentioning

confidence: 99%

The Expression of Prolactin Receptors in Benign Breast Tumors Is Not Associated with Serum Prolactin Level

Kolomiiets

Yazykov

Piddubnyi

et al. 2021

JCM

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The role of prolactin (PRL) and its receptors in the initiation and development of benign breast tumors (BBT) has not been sufficiently studied. An imbalance in the system of hormone homeostasis is crucial in the development of BBT. In particular, an association between elevated prolactin levels and the development of BBT has been reported. Our study showed no significant differences between PRL receptor (PRL-R) expression in BBT tissue under normal and elevated serum PRL levels. There was also no significant correlation between age, PRL-R expression in BBT tissue, intact tissue, and PRL level in the serum. There was a strong significant correlation (p < 0.01; r = 0.92) between PRL-R expression in BBT samples and intact breast tissue, which did not depend on the serum PRL level. There was also no significant difference in the expression of the proliferative marker Ki-67 in BBT tissues from women with normal and elevated levels of serum PRL (p > 0.05). No signs of PRL and its receptors were detected in the BBT cystic fluid women with elevated serum PRL levels. In summary, our prospective study showed that the expression of PRL-R in the tissue of BBT and physiological breast tissue does not depend on the level of serum PRL.

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The human intermediate prolactin receptor is a mammary proto-oncogene

Cited by 20 publications

References 48 publications

Crosstalk between PRLR and EGFR/HER2 Signaling Pathways in Breast Cancer

Crosstalk between PRLR and EGFR/HER2 Signaling Pathways in Breast Cancer

Suppression of Breast Cancer by Small Molecules That Block the Prolactin Receptor

The Expression of Prolactin Receptors in Benign Breast Tumors Is Not Associated with Serum Prolactin Level

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