Defining the Role of Prolactin as an Invasion Suppressor Hormone in Breast Cancer Cells

Abstract

Prolactin hormone (PRL) is well characterized as a terminal differentiation factor for mammary epithelial cells and as an autocrine growth/survival factor in breast cancer cells. However, this function of PRL may not fully signify its role in breast tumorigenesis. Cancer is a complex multistep progressive disease resulting not only from defects in cell growth but also in cell differentiation. Indeed, dedifferentiation of tumor cells is now recognized as a crucial event in invasion and metastasis. PRL plays a critical role in inducing/maintaining differentiation of mammary epithelial cells, suggesting that PRL signaling could serve to inhibit tumor progression. We show here that in breast cancer cells, PRL and Janus-activated kinase 2, a major kinase involved in PRL signaling, play a critical role in regulating epithelial-mesenchymal transformation (EMT), an essential process associated with tumor metastasis. Activation of the PRL receptor (PRLR), achieved by restoring PRL/JAK2 signaling in mesenchymal-like breast cancer cells, MDA-MB-231, suppressed their mesenchymal properties and reduced their invasive behavior. While blocking PRL autocrine function in epithelial-like breast cancer cells, T47D, using pharmacologic and genetic approaches induced mesenchymal-like phenotypic changes and enhanced their invasive propensity. Moreover, our results indicate that blocking PRL signaling led to activation of mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) and transforming growth factor-B/Smad signaling pathways, two major prometastatic pathways. Furthermore, our results indicate that following PRL/JAK2 inhibition, ERK1/2 activation precedes and is required for Smad2 activation and EMT induction in breast cancer cells. Together, these results highlight PRL as a critical regulator of epithelial plasticity and implicate PRL as an invasion suppressor hormone in breast cancer. (Cancer Res 2006; 66(3): 1824-32)

Stat5 activation inhibits prolactin-induced AP-1 activity: distinct prolactin-initiated signals in tumorigenesis dependent on cell context

“…While PRL signals via the Jak2/Stat5 pathway during mammary development are well recognized, relatively little is known about the role of other PRL-initiated signals, and their interrelationships in physiologic and pathologic processes. Recently, PRLactivated Stat5 has been reported to reduce processes associated with tumor aggression in vitro (Sultan et al, 2005;Nouhi et al, 2006), consistent with better prognoses in vivo (Cotarla et al, 2004;Nevalainen et al, 2004), prompting the suggestion that PRL signals may promote a more differentiated tumor phenotype. The present study extends our previous reports of PRL activation of another pathway, driving expression of AP-1 target genes associated with tumor progression.…”

“…High levels of activated Stat5 also are found in a substantial proportion of human breast tumors, which interestingly correlate with a better prognosis (Cotarla et al, 2004;Nevalainen et al, 2004). Recent investigations of breast cancer cell lines in vitro have shown that activated Stat5 inhibits invasion and the epithelial to mesenchymal transition (Sultan et al, 2005;Nouhi et al, 2006). Together, these studies suggest that Stat5 may play complex roles in mammary oncogenesis, augmenting tumor development, but opposing tumor progression.…”

JAK-STAT pathway in carcinogenesis: Is it relevant to cholangiocarcinoma progression?

“…Nevertheless, the summarized data provide a generalized view of the implication of the central cytokine signaling in tumor development of [33] and inhibitory role in metastasis progression [45] ). Moreover, it can help us to decipher new mechanisms of activation of the components of the JAK-STAT pathway like receptor and/ or ligand nuclear localization.…”

“…Moreover, in some models JAK1 and 2 also play an antitumorigenic role [43] . Prl induced activation of JAK2 prevents breast cancer cells mesenchymal transition and acts as an invasion suppressor [44,45] . Reduced phosphorylation of STAT5 in breast cancer highlights patients with a worse prognosis of disease development [46] .…”

Epithelial branching: The power of self‐loathing

“…(4) Indeed, EMT from mammary organoid cultures is used by other researchers as a proxy for malignant invasion (as in mammary carcinoma) rather than normal development. (8)(9)(10) It is possible, therefore, that Nelson et al…”