Cellular retinol binding protein-1 (CRBP1) is up-regulated in response to parity-induced changes in the mammary gland.

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Despite current advances in breast cancer it is still the most common type of cancer death seen in women. Of interest, women who give birth to a child before 24 years of age demonstrate a decrease in their overall lifetime risk of developing breast cancer. In rodents, elevated and sustained levels of estrogen (E) and progesterone (P) similar to pregnancy can impart many of these important changes attributed to this protection. Using an in vitro mammary gland whole organ culture (WOC) system we have previously found that E and P induced the up-regulation of Cellular Retinol Binding Protein-1 (CRBP1), a gene which is often hyper-methylated during breast cancer progression. CRBP1 is under-expressed in 24% of human breast carcinomas, and has also been shown to suppress proliferation and anchorage-independent survival of a breast cancer cell line (Farias et al.).This suggests that this protein may have a dual function in retinoic acid metabolism and tumor suppression. To continue these studies we wanted to see if changes in the level of CRBP1 in the mammary gland were persistent after parity. A persistent up-regulation would be necessary if the gene were to have a true protective role. CRBP1 expression was examined in parous and age matched nulliparous mice, and it was found that CRBP1 RNA and protein levels are in fact significantly up-regulated in parous mice compared to nulliparous. To see if the change in CRBP1 was relevant to humans as well, we first examined CRBP1 expression in immortalized human breast epithelial cells, 76N TERT cells, treated with E+P. Both RNA and protein levels of CRBP1 were up-regulated in response to treatment with E+P in 76N TERTs. Finally, we examined breast tissue from a variety of patients undergoing reduction mammoplasty for differences in CRBP1 protein expression. We found that CRBP1 protein is significantly increased in parous patients compared to nulliparous patients. Overall this data demonstrates that CRBP1 levels are increased persistently after parity in both rodents and humans, thereby suggesting that it has the appropriate expression profile to be a gene of interest for parity-induced protection. Taken together with its loss during the progression to breast cancer, and suggestions of a tumor suppressor role in the literature, we believe that this protein may be of significant importance for protection within the mammary gland. Farias, E. F. et al. 2005 JNCI 97: 21-29