Utilizing The Novel Manganese-Induced Precocious Puberty Rat Model Identifies Progesterone Receptor as an Important Mediator Between Female Puberty and Breast Cancer
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Precocious puberty (PP) is a serious endocrine disorder associated with an increased risk for development of numerous diseases including breast cancer (BC). It is hypothesized that alterations in steroidal signaling during puberty may be a contributing factor to BC development and progression. Until now, there hasn't been a strong model to study this relationship. Our group has established manganese (Mn) as a nontoxic, natural activator of the pubertal process. When exposed to a low, supplemental dose early in life, Mn can advance the onset of puberty in female rats by centrally stimulating the release of the normal hormonal milieu that drives pubertal development, including estradiol (E2). Using this model, we recently demonstrated that Mninduced PP (MnPP) accelerates E2regulated mammary gland (MG) development and ductal differentiation in prepubertal female rats, resulting in sustained proliferation of mammary luminal epithelial cells and adult hyperplasia. However, we have yet to identify the molecular underpinnings that result in the development of this phenotype. Therefore we aimed to elucidate key steroidal markers that contribute to the uncharacteristic phenotype observed in the adult MG of precociously developed female rats. Sprague Dawley female rats were exposed daily to 10mg/kg manganese chloride (MnCl2) or saline (control) via gastric gavage from postnatal day (PND) 12 to PND 30. Blood and MGs were collected on PNDs 30 and 120. Western blot (WB) analysis revealed a significant increase in protein expression of cmyc (p<0.05) and amphiregulin (AREG) (p<0.05) in Mntreated females when compared to controls at PND 30, but no change in expression of cyclin D1. In addition to a previously observed increase in estrogen receptor (ER) expression at PND 120, WB confirmed a significant increase in expression of progesterone receptorbeta (PR) (p<0.05) in the MG of Mntreated females. Immunohistochemistry visually confirmed the changes in protein expression of ER and PR in the glands at PND 120. Furthermore, luciferase reporter assays indicated that Mn does not directly activate ER, thus reinforcing that the observed changes in MG development are centrally driven. While preliminary, these data suggest that E2regulated proteins, including AREG and cmyc, drive the initial developmental changes observed in the prepubertal MG, while implicating a more dominant role of progesterone (P4) in the hyperplasic phenotype observed at PND 120. These findings are supported by previous studies suggesting that PR has a greater impact on mitogenic potential and cell cycle deregulation than ER in the adult MG and in early BC. Collectively, our findings suggest that PP may increase BC risk through PRmediated events in the MG, resulting in deregulation and premalignant transformation.Support or Funding InformationThis work was supported by NIEHS grant ESO13143 awarded to WLD and NIGMS grant 1R25GM100866 awarded to RKD
