Abstract
Simple SummaryProlactin receptor (PRLR) and epidermal growth factor receptor (EGFR/ERBB) signaling pathways have a crucial role in the development of mammary glands and breast carcinogenesis. In this review, we have provided ample evidence to support the significant role for PRLR and EGFR/HER2 signaling crosstalk in breast cancer. Recent studies from our lab and other finding also recognize how these two receptors work together to induce hyperactivation of their downstream signaling kinases that overlap with each other and in turn further induce target genes and other pro-oncogenic factors. Prolactin through PRLR can activate both EGFR and HER2 downstream signaling pathways which in turn leads to activation of other oncogenic growth factors that promote growth, survival, and proliferation of breast cancer cells. The crosstalk between PRLR and EGFR/HER2 signaling is an additional route that magnifies the actions of their ligands, and further promote tumor growth. This may be responsible for endocrine resistance in breast cancer patients resulting in tumor relapse.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.
Highlights
Epidermal growth factor receptors (EGFR/ERBB) and prolactin receptor (PRLR) signaling have an important role in mammary gland morphogenesis and carcinogenesis
In large epidemiological studies it has been well documented that elevated circulating PRL levels are correlated with increased breast cancer risk and metastasis in premenopausal women and this risk is greater for estrogen receptor (ER)+ breast cancer and lymph node-positive tumors [9,10]
We have demonstrated that PRL/PRLR induces HER2 phosphorylation at Tyr residues 1221 and 1222 through JAK2, activation of downstream PI3K/AKT pathway in both MCF-7 and T47D cells [31]
Summary
Epidermal growth factor receptors (EGFR/ERBB) and prolactin receptor (PRLR) signaling have an important role in mammary gland morphogenesis and carcinogenesis. Binding of trastuzumab to the external domain of HER2 receptor prevents HER2 homo- and heterodimerization and leads to disruption of downstream HER2 signaling pathways, blocking proliferation of the breast cancer cells [3,5,6,7]. Another hormone receptor which is overexpressed in most of the ER+ breast tumors is the PRLR. Contrary to the believed role of PRLR in breast cancer progression, recent studies have indicated that PRL exerts anti-tumorigenic effects in HER2 positive breast cancer cells through regulation of stemness [15,16]. Provides a rationale for the use of combined therapeutic inhibitors targeting receptors and/or associated signaling pathways in the treatment of invasive breast cancer
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