Breast cancer is the second leading cause of death of women in the United States, warranting further investigation into preventative therapies. It has been well documented that early pregnancy results in a lifetime decreased risk of breast cancer in humans and mounting evidence suggests that the retinoic acid pathway may play an important role in this protective effect. Cellular retinol binding protein-1 (CRBP1) is an essential component of the retinoic acid pathway and we propose that it plays an important role in pregnancy-induced protection against breast cancer. In order to investigate the role of CRBP1 in parity-induced protection against breast cancer, we utilized both mouse and human mammary epithelial cells. We examined the effect that pregnancy has on CRBP1 expression, how CRBP1 is regulated by growth promoting and inhibiting agents, if loss of CRBP1 is essential for the induction of the apoptotic pathway, and how CpG methylation of key breast cancer genes relates to known risk factors for the disease. Based on our study, CRBP1 is persistently upregulated in response to pregnancy in the mouse mammary gland at both the RNA and protein levels. Using a cell culture model, we established that CRBP1 is regulated by chemical agents that both promote and inhibit cellular growth. Utilizing CRBP1 knockout mice, we demonstrated that CRBP1 is not essential for induction of radiation induced apoptosis in parous mice. Finally, through methylation analysis, we examined how known breast cancer risk factors correlate to CpG methylation of three important genes for breast cancer and noted interesting trends that warrant future study.

La Retinosi Pigmentària (RP) és el terme aplicat a un grup de degeneracions de la retina clínicament i genèticament heterogeni. A nivell clínic es caracteritza per la presència d'una ceguesa nocturna i una constricció dels camps visuals, conduint a una pèrdua total de la visió. La RP pot heretar-se seguint la forma autosòmica dominant (RPAD), autosòmica recessiva (RPAR), i lligada al cromosoma X (RPLX), o seguint una forma d'herència digènica.Previs estudis han descrit mutacions en els gens PDEB, ABCA4, TULP1 i CNGA1 en un petit percentatge de famílies espanyoles amb RPAR. Aquestes dades indiquen que altres gens poden estar involucrats en la patologia de les restants famílies analitzades, emfatitzant l'elevada heterogeneïtat genètica present en aquesta malaltia i reforçant la hipòtesi que en la RPAR no hi ha un únic gen principal sinó que existirien varis gens on cadascun d'ells explicaria un petit número de casos. Hem analitzat la implicació de cinc gens addicionals que codifiquen per: la proteïna d'unió al retinaldehid (gen RLBP1), el receptor acoplat a proteïna G de l'EPR (gen RGR), la proteïna cel·lular d'unió al retinol (gen CRBP1), crumbs homologue 1 (gen CRB1) i la usherina (gen USH2A) en famílies espanyoles amb RPAR.Malgrat que en els gens RLBP1, RGR i CRBP1 s'han detectat diversos polimorfismes tant a nivell exònic com intrònic, no s'ha trobat cap mutació associada a la malaltia, suggerint que aquests gens probablement no estarien implicats en la patologia d'aquest grup de famílies espanyoles amb RPAR. En canvi, l'anàlisi mutacional dels gens CRB1 i USH2A ha permès la identificació de vàries variants rares, polimorfismes intrònics i diverses mutacions patològiques en el grup analitzat de pacients espanyols amb RPAR. L'ample rang de fenotips associats amb les mutacions trobades en els gens CRB1 i USH2A reflexa que les relacions entre les mutacions patològiques i el fenotip de la malaltia esdevenen cada cop més complexes.La síndrome d'Usher és la forma més freqüent de la RP sindròmica. Clínicament es caracteritza per una sordesa congènita i neurosensorial associada a RP. En un grup de pacients afectats amb la síndrome d'Usher tipus II es van detectar vàries mutacions patològiques en el gen USH2A. Els diferents fenotips associats amb les mutacions en el gen USH2A van revelar una important heterogeneïtat clínica en aquest grup de pacients. Aquests resultats junt amb els descrits en altres treballs confirmen una gran heterogeneïtat fenotipíca presentada per les mutacions en el gen USH2A, que va des de diferents tipus de la síndrome d'Usher fins a la RP no sindròmica. / Retinitis Pigmentosa (RP) is the term applied to a clinically and genetically heterogeneous group of retinal degeneration. Clinically is characterised by night blindness and constriction of visual fields, leading to complete blindness. RP can be inherited in either an autosomal dominant (ADRP), autosomal recessive (ARRP), X-linked (XLRP), or digenic mode. Previous studies have described mutations in the PDEB, ABCA4, TULP1 and CNGA1 genes in a small percentage of Spanish ARRP families. These data indicates that other than these genes may be involved in the remaining families analysed, emphasising the genetic heterogeneity of the disease and reinforcing the hypothesis that in ARRP there is no a major gene but several genes may account individually for a small number of cases.We analysed the involvement of five additional genes: the retinaldehyde-binding protein 1 (RLBP1 gene), the RPE retinal G protein-coupled receptor (RGR gene), the cellular retinol-binding protein 1 (CRBP1 gene), the crumbs homologue 1 (CRB1 gene) and usherin (USH2A gene) in ARRP Spanish families. Several exonic and intronic polymorphisms were detected in the RLBP1, RGR and CRBP1 genes. However, no disease-causing mutations were found, suggesting that these genes be most probably not involved in the disease in this set of ARRP Spanish pedigrees. In contrast, the mutational analysis of the CRB1 and USH2A genes allowed the identification of a number of rare sequence variants and intronic polymorphisms, and of several pathogenic mutations in the group of ARRP Spanish patients analysed. The wide range of phenotypes associated with mutations found in CRB1 and USH2A genes underlines how the relationship between pathogenic mutations and disease phenotype is becoming increasingly complex.The Usher syndrome is the most frequent syndromic RP. Clinically is characterised by congenital sensorineural hearing loss and RP. Several pathogenic mutations in USH2A gene were detected in a group of Usher syndrome type II patients. Different phenotypes associated with mutations in USH2A gene revealed an important heterogeneity clinical in this group of patients. The results presented here together with that in previous reports confirm a great phenotypic heterogeneity arising from mutations in USH2A gene, which ranges from distinct types of Usher syndrome to non-syndromic retinitis pigmentosa.