Prolactin Does Not Require Insulin-Like Growth Factor Intermediates but Synergizes with Insulin-Like Growth Factor I in Human Breast Cancer Cells

Abstract

Insulin-like growth factor (IGF)-II is a required intermediate for prolactin-induced up-regulation of cyclin D1 and proliferation in normal murine mammary epithelial cells in vivo and in vitro. However, we have recently shown that prolactin can rapidly induce cyclin D1 protein expression and subsequent proliferation in the MCF-7 human breast cancer cell line, suggesting that prolactin actions can be independent of IGFs in breast disease. Here, we investigate the relationship between these factors and show that prolactin up-regulated transcript levels of both IGF-I and IGF-II, but only after increases in cyclin D1 protein were observed. Moreover, prolactin increased cyclin D1 in the presence of the IGF-I receptor neutralizing antibody AIR3. However, on cotreatment, IGF-I and prolactin elicited cooperative phosphorylation of extracellular signal -regulated kinases 1 and 2 and protein kinase B/AKT, but not signal transducer and activator of transcription 5. This interaction extended to increased activation of activating protein-1 enhancer elements, phosphorylation of glycogen synthase kinase 3B, induction of cyclin D1, and ultimately, increased cell number. It also increased invasive behavior, which correlated with elevated matrix metalloproteinase-2 transcript levels. Interestingly, prolactin augmented phosphorylation at Tyr 1135 and Tyr 1136 of IGF-I receptor on cotreatment with IGF-I, although prolactin alone had no effect. Together, these data indicate that strong cooperative cross talk between prolactin and IGF-I augments biological processes associated with neoplastic progression, with implications for therapeutic strategies.

Stiff Collagen Matrices Increase Tumorigenic Prolactin Signaling in Breast Cancer Cells

“…Tyrosine kinase inhibitors, which block activation of ERK1/2 and AKT, inhibit both proliferation and collagen synthesis in tumor-associated fibroblasts (77). In light of the ability of PRL to potently cooperate with growth factors to activate these signaling pathways (15,16), these interactions deserve further investigation. Together, the altered PRL-initiated signals and consequences for cell behavior described in the current study in the context of the literature begin to define a feed-forward loop in which PRL actions in breast cancer not only are altered by matrix stiffness but where PRL itself directly contributes to the density and organization of the matrix to promote the progression of breast cancer.…”

“…PRL also initiates strong phosphorylation of ERK1/2 in breast cancer cells in vitro (7) and in the murine mammary gland in vivo (14). Moreover, it cooperates with growth factors to prolong phosphorylated ERK1/2 (pERK1/2) (15) associated with increased matrix metalloproteinase (MMP) expression and invasion (16). We have shown previously that PRL signals to STAT5 and mitogen-activated protein kinase-stimulated activating protein 1 are inversely related in vitro and in vivo (13,17).…”

Prolactin Enhances Insulin-like Growth Factor I Receptor Phosphorylation by Decreasing Its Association with the Tyrosine Phosphatase SHP-2 in MCF-7 Breast Cancer Cells

“…We have recently described cooperative cross-talk between PRL and IGF-I in breast cancer cells (7). Alone, IGF-I stimulates proliferation of mammary epithelial cells, contributing to ductal branching and elongation, and promotes survival of alveolar structures during lactation (11,12).…”

Neutralization of Prolactin Receptor Function by Monoclonal Antibody LFA102, a Novel Potential Therapeutic for the Treatment of Breast Cancer

“…The signaling pathway most often associated with PRLR function is the Jak2/Stat5 pathway, although other prosurvival and anti-apoptotic signaling cascades are also known to be triggered in cancer cell lines, including Jak1/Stat3, phosphoinositide 3-kinase (PI3K)/Akt, and Raf/MEK/ERK (8)(9)(10). PRLR has also been observed to cross-talk with other growth factor and steroid receptor signaling pathways, including insulin-like growth factor-1 receptor (IGF1R), EGF receptor (EGFR), HER2, and ERa (11)(12)(13)(14)(15), suggesting opportunities for synergy between an anti-PRLR therapeutic and other targeted agents in human breast cancer.…”