Exploring ovarian-derived hormone STC1 as the mediator of the protective effect of breast feeding against breast cancer.

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Pregnancy imposes remarkable changes to the breast; 1- during pregnancy, impressive cellular proliferation and differentiation of the ductal tree is observed, 2- during lactation, the ultimate function of breast and 3- during post-lactation involution that is associated with tissue remodeling and inflammation. Interestingly both the proliferation during pregnancy and the inflammation during involution engage signaling pathways associated with cancer and indeed, the risk of breast cancer increases following pregnancy. However, extended lactation reduces that risk but the molecular mechanism of the protective effect of breastfeeding remains unknown. Based on our preliminary data, we postulate that the ovarian-derived hormone stanniocalcin 1 (STC1) is the potential mediator of the protective effect of breastfeeding. STC 1 is a secreted hormone produced mainly by the ovaries during lactation. It has been found to act as an inhibitor of the protease PAPP-A, Pregnancy-Associated Plasma Protein A. PAPP-A is a secreted protease that promotes proliferation through IGF signaling by degrading IGFBP- 5 during involution, promotes immune evasion and we reported takes advantage of the microenvironment of involution to promote metastasis. PAPP-A is frequently overexpressed in the breast cancers and we have generated the first mouse model of PAPP-A driven mammary tumors. Importantly for this application, we found that long lactation prevents the formation of PAPP-A-driven tumors. Our hypothesis is that ovarian-derived STC1 produced during lactation reach the mammary gland through the circulation, saturates and inhibits PAPP-A and is the mechanism underlying the protective effect of long lactation. We present preliminary data that incubation of PAPP-A with serum taken from lactating females, but not from non-lactating females, inhibits its ability to degrade IGFBP-5. Further, depletion of STC1 from lactating -female serum blocks this effect. The goal of this exploratory award is to test if transfusions of blood from lactating donors into non- lactating recipients during post-partum involution, can mimic the protective effect of lactation in these recipient females. In order to test this possibility, we propose the following aims; Specific aim 1: Characterize potential fluctuations in the serum concentration and activity of STC1 throughout lactation and determine if transfusions of blood from lactating females can mimic the protective effect of long lactation in wild-type non-lactating mice. Specific aim 2: Testing the protective effect of ovarian STC1 against PAPP-A driven mammary tumors. In this aim, we will perform the same experiment described in aim 1 but in the MMTV-PAPP-A transgenic mice with two exceptions. First, since this model is much more aggressive than normal involution without prior lactation, we will use a more intense scheduling of transfusions. Second, since 75% of PAPP-A transgenic mice develop post- partum mammary tumors when females do not lactate, we will monitor tumor formation.