**4. Nrg1/ErbB receptor inhibition as a potential clinical management of prolactinoma**

The role of Nrg1-mediated autocrine, paracrine, or juxtacrine signaling in several aspects of cancer biology suggests that it is a potential target for tumor therapy. Success with a combined therapeutic antibody and sheddase inhibitor treatment has been demonstrated in the mammary cancer MCF- 7 cell line, in which the administration of INCB7839 (a second generation sheddase inhibitor) with Lapatinib prevents the growth of ErbB2 positive BT474- SC1 human breast cancer xenografts in vivo (Witters et al., 2008). Gefitinib, a tyrosine kinase inhibitor, has also been reported to suppress Nrg1-mediated ErbB2/ErbB3 signaling to PRL (Vlotides et al., 2008, 2009). A recent investigation has also revealed that Lapatinib, an ErbB2 inhibitor, possesses additional effects in the suppression of PRL expression, and oral Lapatinib treatment triggers the shrinkage of estrogen-induced prolactinomas in rats (Fukuoka et al., 2010). Thus, the co-localization of Nrg1 with ErbB2 in partial prolactinomas suggests that inhibiting Nrg1 expression or abolishing its binding ability might also have similar effects in inhibiting Nrg1-dependent ErbB receptor activation and prolactinoma progression. In one of our studies, five human prolactinoma tissues were stained for both Nrg1 and ErbB2. All samples demonstrated positive staining for Nrg1, and co-expression of both molecules was observed in one sample (Zhao et al., 2011b). Additional prolactinoma samples should be recruited to stress further the role of Nrg1/ErbB receptor singling in future investigations. The findings regarding the endogenous expression of Nrg1 and an Nrg1-mediated autocrine/paracrine mechanism in GH3 cells have expanded previous results and reveal Nrg1 as a potential diagnostic serological marker for prolactinoma. In addition, a therapeutic approach involving the direct functional inhibition of Nrg1 might be a viable clinical treatment for PRL-secreting pituitary tumors.

#### **5. Conclusions and perspectives**

92 Prolactin

ErbB3 receptor activation was also observed. However, downregulation of Nrg1 has no effects on GH secretion. Thus, Nrg1 may modulate PRL secretion from GH3 cells in an

**Figure 6.** Schematic diagram illustrating the hypothesized model for Neuregulin-1 (Nrg1) on PRL

**4. Nrg1/ErbB receptor inhibition as a potential clinical management of** 

The role of Nrg1-mediated autocrine, paracrine, or juxtacrine signaling in several aspects of cancer biology suggests that it is a potential target for tumor therapy. Success with a combined therapeutic antibody and sheddase inhibitor treatment has been demonstrated in the mammary cancer MCF- 7 cell line, in which the administration of INCB7839 (a second generation sheddase inhibitor) with Lapatinib prevents the growth of ErbB2 positive BT474- SC1 human breast cancer xenografts in vivo (Witters et al., 2008). Gefitinib, a tyrosine kinase inhibitor, has also been reported to suppress Nrg1-mediated ErbB2/ErbB3 signaling to PRL (Vlotides et al., 2008, 2009). A recent investigation has also revealed that Lapatinib, an ErbB2 inhibitor, possesses additional effects in the suppression of PRL expression, and oral Lapatinib treatment triggers the shrinkage of estrogen-induced prolactinomas in rats (Fukuoka et al., 2010). Thus, the co-localization of Nrg1 with ErbB2 in partial prolactinomas suggests that inhibiting Nrg1 expression or abolishing its binding ability might also have similar effects in inhibiting Nrg1-dependent ErbB receptor activation and prolactinoma progression. In one of our studies, five human prolactinoma tissues were stained for both Nrg1 and ErbB2. All samples demonstrated positive staining for Nrg1, and co-expression of both molecules was observed in one sample (Zhao et al., 2011b). Additional prolactinoma samples should be recruited to stress further the role of Nrg1/ErbB receptor singling in

autocrine, paracrine/juxtacrine manner (See Fig 6).

regulation. A, autocrine; P, paracrine; J, juxtacrine.

**prolactinoma** 

Among a series of regulators of PRL, the emerging role of Nrg1 is rather new, but important. Overexpression of Nrg1 and its cognate receptor ErbB2, as well as their co-localization provides the promising therapeutic method to control prolactinoma and hyperprolactinemia. Such a clinical purpose can be achieved by 1) Nrg1 receptor inhibitor, such as Erlotinib, Lapatinib et al.; 2) neutralizing antibody against Nrg1 and 3) their combination. Additionally, Nrg1-mediated autocrine/paracrine mechanism in GH3 cells have expanded previous results and reveal Nrg1 as a potential serological marker not only for prolactinoma diagnosis, but for prognosis evaluation post operation. In addition, a therapeutic approach involving the direct functional inhibition of Nrg1 might be a viable clinical treatment for PRL-secreting pituitary tumors. To avoid the side effects, such as affecting the physiological function of circulating Nrg1 brought by intravenous administration of anti-Nrg1 antibody, the therapeutic hypothesis may be established by intratumoral (i.t.) injection of the therapeutic antibody in patients, whose prolactinomas are highly resistant to chemotherapy or in whom the tumor location can lead to high surgery risk. It has recently been reported that experimental i.t. injections with ErbB2 targeted gold nanoparticles (AuNPs) resulted in high tumor retention with low systemic exposure and represents an attractive delivery strategy (Chattopadhyay et al., 2012).

### **Author details**

Weijiang Zhao *Center for Neuroscience, Shantou University Medical College, Shantou, Guangdong Province, China Cedars-Sinai Medical Center, Los Angeles, California 90048, USA* 
