Biological Significance of Prolactin in Gynecologic Cancers

Abstract

There is increasing evidence that prolactin (PRL), a hormone/ cytokine, plays a role in breast, prostate, and colorectal cancers via local production or accumulation. Elevated levels of serum PRL in ovarian and endometrial cancers have been reported, indicating a potential role for PRL in endometrial and ovarian carcinogenesis. In this study, we show that serum PRL levels are significantly elevated in women with a strong family history of ovarian cancer. We show dramatically increased expression of PRL receptor in ovarian and endometrial tumors as well as in endometrial hyperplasia, signifying the importance of PRL signaling in malignant and premalignant conditions. PRL mRNA was expressed in ovarian and endometrial tumors, indicating the presence of an autocrine loop. PRL potently induced proliferation in several ovarian and endometrial cancer cell lines. Binding of PRL to its receptor was followed by rapid phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, mitogen-activated protein kinase/ ERK kinase 1, signal transducer and activator of transcription 3, CREB, ATF-2, and p53 and activation of 37 transcription factors in ovarian and endometrial carcinoma cells. PRL also activated Ras oncogene in these cells. When human immortalized normal ovarian epithelial cells were chronically exposed to PRL, a malignant transformation occurred manifested by the acquired ability of transformed cells to form clones, grow in soft agar, and form tumors in severe combined immunodeficient-beige mice. Transformation efficiency was diminished by a Ras inhibitor, providing proof that PRL-induced transformation uses the Ras pathway. In summary, we present findings that indicate an important role for PRL in ovarian and endometrial tumorigenesis. PRL may represent a risk factor for ovarian and endometrial cancers. [Cancer Res 2009;69 (12):5226-33]

Expression, activation, and role of AKT isoforms in the uterus

“…This change is accompanied by the secretion of various proteins such as prolactin (PRL) as well as insulin-like growth factorbinding protein 1 (IGFBP1). PRL has been shown to be an inhibitor of apoptosis in various tissues (Al-Sakkaf et al 2000, Gado et al 2002, Krishnan et al 2003 as well as an increasingly relevant tumor biomarker in gynecological cancers (Asai-Sato et al 2005, Levina et al 2009). The antiapoptotic effects of PRL on decidual cells also appear to be AKT dependent.…”

Cancer risk in hyperprolactinemia patients: a population-based cohort study

“…However, the role of PRL in human prostate pathology is not clarified and epidemiological data on PRL and risk of prostate cancer is sparse (15,16). Furthermore, it has been suggested that locally produced PRL could play a role in tumor development in gynecological (17), colorectal (18), tongue (19), and hematopoietic cancer (20,21).…”

Increased expression of the prolactin receptor is associated with malignant laryngeal tumors

“…However, the mechanisms underlying the proliferation of this form of cancer are not yet fully understood. Alterations in the expression of prolactin (PRL) and certain signaling intermediate levels can contribute to the development and progression of certain types of cancer, particularly in hormone-dependent organs (e.g., breast, endometrium, prostate), but most likely at other primary sites as well (6)(7)(8). The diverse activities of PRL are mediated by its receptor (PRLR) and it involves the activation of a number of signaling pathways including Jak2-STAT (9), PI3K (10) and MAPK (11,12).…”