Lrig1 is the founding member of the “Lrig” family and has been implicated in the negative regulation of several oncogenic receptor tyrosine kinases including ErbB2. Lrig1 is expressed at low levels in several cancer types but is over-expressed in some prostate and colorectal tumors. Given this heterogeneity, whether Lrig1 functions to suppress or promote tumor growth remains a critical question. Previously, we found that Lrig1 was poorly expressed in ErbB2-positive breast cancer, suggesting that Lrig1 has a growth inhibitory role in this tumor type. However, breast cancer is a complex disease, with ErbB2-positive tumors accounting for just 25% of all breast cancers. To gain a better understanding of the role of Lrig1 in breast cancer, we examined its expression in estrogen receptor alpha (ERα)-positive disease which accounts for the majority of breast cancers. We find that Lrig1 is expressed at significantly higher levels in ERα-positive disease as compared to ERα-negative disease. Our study provides a molecular rationale for Lrig1 enrichment in ERα-positive disease by demonstrating that Lrig1 is a target of ERα. Estrogen stimulates Lrig1 accumulation and disruption of this induction enhances estrogen-dependent tumor cell growth, suggesting that Lrig1 functions as an estrogen regulated growth suppressor. Additionally, we find that Lrig1 expression correlates with prolonged relapse-free survival in ERα-positive breast cancer, identifying Lrig1 as a new prognostic marker in this setting. Finally, we demonstrate that ErbB2 activation antagonizes ERα-driven Lrig1 expression, providing a mechanistic explanation for Lrig1 loss in ErbB2-positive breast cancer. This work provides strong evidence for a growth inhibitory role for Lrig1 in breast cancer.

Background: Lrig1 is a negative regulator of oncogenic receptor tyrosine kinases. Results: Lrig3 opposes Lrig1 negative regulatory action and enhances ErbB receptor stability. Conclusion: Lrig1 and Lrig3 oppose one another. Significance: Despite structural homology, Lrig1 and Lrig3 are functionally distinct.

Delivery of biologics via cerebrospinal fluid (CSF) has demonstrated potential to access the tissues of the central nervous system (CNS) by circumventing the blood-brain barrier and blood-CSF barrier. Developing an effective CSF drug delivery strategy requires optimization of multiple parameters, including choice of CSF access point, delivery device technology, and delivery kinetics to achieve effective therapeutic concentrations in the target brain region, whereas also considering the biologic modality, mechanism of action, disease indication, and patient population. This review discusses key preclinical and clinical examples of CSF delivery for different biologic modalities (antibodies, nucleic acid-based therapeutics, and gene therapy) to the brain via CSF or CNS access routes (intracerebroventricular, intrathecal-cisterna magna, intrathecal-lumbar, intraparenchymal, and intranasal), including the use of novel device technologies. This review also discusses quantitative models of CSF flow that provide insight into the effect of fluid dynamics in CSF on drug delivery and CNS distribution. Such models can facilitate delivery device design and pharmacokinetic/pharmacodynamic translation from preclinical species to humans in order to optimize CSF drug delivery to brain regions of interest.