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

SIMPLE SUMMARY: Prolactin 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. ABSTRACT: 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.