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.
