Abstract
Abstract Introduction: Parous rats treated with chemical carcinogen develop a low incidence of overt mammary cancers compared to that in carcinogen-treated nulliparous rats. Examination of the mammary glands at necropsy 12 months after carcinogen treatment revealed that a high percentage of the parous rats had preneoplastic mammary lesions. These studies demonstrate that in parous rats, initiation of mammary carcinogenesis occurs at a high efficiency, although the systemic and local environment is inadequate for promotion to overt cancers. Stem cells have been implicated as the target cells for tumor initiation. In this study we investigated if parity altered the mammary stem cells. Materials and Methods: Nulliparous and parous parous were euthanized and the preneoplastic mammary lesions were surgically removed under a dissection microscope. The lesions were dissociated using the collagenase digestion method. After digestion the cells were separated using the percoll gradient. The enriched epithelial cell population was cultured and sorted for stem cells using ALDH, CD44, CD24 as markers. Sphere formation assays was established using 5000 cells/well on ultra-low attachment 6-well plates. For self-renewal assay, the 1st generation spheres was dissociated using Accutase, counted and replated in the same media as single cells with a plating density of 5000 cells/well. The same process was followed for the subsequent generations. In another set of experiments stem cells were treated with growth hormone (GH) and prolactin (PRL) to identify the role of these two mammogenic hormones on the mammary stem cells. Using the stem cells we performed the limiting dilution analysis to estimate the tumor forming capacity of the initiated mammary stem cells. Results: The sphere forming capacity of parous mammary stem cells was significantly reduced compared to nulliparous mammary stem cells. In addition, the self-renewing abilities were also remarkably decreased. Treatment with GH and PRL restored the sphere forming and self-renewing capabilities of parous mammary stem cells similar to nulliparous mammary stem cells. Further, the limiting dilution assay also demonstrated that parity altered the mammary stem cells making them less capable of forming tumors. Conclusion: Parity significantly altered the characteristics of the mammary stem cells rendering them to be resistant to mammary tumorigenesis. GH and PRL were able to increase stemness and favor mammary tumorigenesis in parous rats. Further research is required to delineate the mechanism by which parity alters the stemness characteristics of mammary stem cells reducing the risk of mammary cancers. Citation Format: Ramadevi Subramani, Adriana Estrada, Sheryl Rodriguez, Seeta Poudel, Jesse Foskey, Cynthia Jimenez, Kenneth Smith, Mark Shahinian, Abdallah Yazadi, Tugba Mehmetoglu-Gurbuz, Jackelyn Rocha, Rajkumar Lakshmanaswamy. Parity reduces the risk of mammary cancer by altering the characteristics of mammary stem cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-11-02.
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