John P. Lydon, Ph.D.
Department of Molecular and Cellular Biology
Ph.D.: National University of Ireland, Galway, Ireland
Postdoctoral training: Baylor College of Medicine, Houston
Progesterone Signaling in Mammary Gland Development and Tumorigenesis
Despite progesterone's established role in female reproductive biology, the functional contribution of this ovarian steroid hormone in mammary gland development and tumorigenesis is less well understood. To address this issue, our laboratory group has generated and utilized state-of-the-art genetically engineered mouse models to study progesterone receptor action in vivo. Our past studies have shown that abrogation of progesterone receptor function in the murine mammary epithelium results in severe impairments in epithelial ductal side-branching and alveologenesis, underscoring a pivotal role for progesterone receptor mediated signaling in normal mammary morphogenesis. Importantly, the lack of the progesterone signal renders the mouse significantly less susceptible to mammary tumorigenesis. Our cancer studies reinforce and extend the importance of progesterone and its receptor in mammary tumor promotion. Significantly, our findings concur with recent clinical trials and observational studies that show progestin inclusion in postmenopausal hormone therapy poses a significant risk for breast cancer in later life.
For our investigator group, understanding the cellular and molecular principles that underpin progesterone’s role in mammary development and tumorigenesis is now an important research priority. Toward this goal, our research team is currently employing innovative gene-discovery approaches (including microarray, genome-wide ChIP-seq, RNA-seq, and proteomics) along with cell-based and mouse models to reveal and validate a number of critically important genes, pathways, and networks that mediate normal progesterone responses in the mammary epithelium. Our future research objectives will be to determine whether early progesterone-initiated mammary tumor progression also requires these same downstream molecular targets (or a subset thereof). In sum, our research program promises to furnish important new molecular insights into progesterone's developmental role in the normal mammary gland as well as provide a more comprehensive mechanistic understanding of how progesterone influences mammary tumor progression at the cellular and molecular level.
Progesterone is required for the promotion of hormone-dependent breast cancer in the mouse.
Panel A shows a whole-mount of a mammary gland from a transgenic mouse which is predisposed to hormone-dependent breast cancer. Note the emergence of hyperplastic foci (as indicated by the blue arrows). These focal areas of epithelial hyperplasia progress to hormone-dependent palpable mammary tumors with time. Using state-of-the-art gene-targeting approaches, this mouse was genetically modified so that progesterone receptor expression could be tracked in situ (indicated by blue spots). Compared to normal areas of the mammary gland, note the high concentration of mammary epithelial cells within hyperplastic foci which express the progesterone receptor (Panel B (blue arrow)). This observation supports our proposal that the development and progression of this tumor-type requires the progesterone growth stimulus. The future goals of our laboratory are to define the cellular and molecular mechanisms that underlie progesterone's role in normal breast development and to determine how these normal processes change with breast cancer initiation and progression. We believe this information will not only aid in furthering our mechanistic understanding of progesterone's role in mammary gland biology and neoplasia in the mouse, but may provide important new insights into the current controversies which surround progesterone's role in human breast cancer.
Baylor College of Medicine
One Baylor Plaza, DeBakey M732A
Houston, TX 77030
- Mukherjee A, Soyal SM, Li J, Ying Y, He B, Demayo FJ, Lydon JP. (2010). Targeting RANKL to a specific subset of murine mammary epithelial cells induces ordered branching morphogenesis and alveologenesis in the absence of progesterone receptor expression. FASEB J. Jul 6. [Epub ahead of print] PubMed PMID: 20605949.
- Lydon JP. Stem cells: Cues from steroid hormones. (2010). Nature. Jun 10;465(7299):695-6. PubMed PMID: 20535190.
- Lydon JP, Edwards DP. (2009). Finally! A model for progesterone receptor action in normal human breast. Endocrinology. Jul;150(7):2988-90. PubMed PMID: 19549883; PubMed Central PMCID: PMC2703515.
- Fernandez-Valdivia R, Mukherjee A, Ying Y, Li J, Paquet M, DeMayo FJ, Lydon JP. (2009). The RANKL signaling axis is sufficient to elicit ductal side-branching and alveologenesis in the mammary gland of the virgin mouse. Dev Biol. Apr 1;328(1):127-39. Epub 2009 Jan 23. PubMed PMID: 19298785.
- Fernandez-Valdivia R, Mukherjee A, Creighton CJ, Buser AC, DeMayo FJ, Edwards DP, Lydon JP. (2008). Transcriptional response of the murine mammary gland to acute progesterone exposure. Endocrinology. c;149(12):6236-50. Epub 2008 Aug 7. PubMed PMID: 18687774; PubMed Central PMCID: PMC2613059.
- Jeong JW, Lee HS, Franco HL, Broaddus RR, Taketo MM, Tsai SY, Lydon JP, DeMayo FJ. (2009). beta-catenin mediates glandular formation and dysregulation of beta-catenin induces hyperplasia formation in the murine uterus. Oncogene. Jan 8;28(1):31-40. Epub 2008 Sep 22. PubMed PMID: 18806829; PubMed Central PMCID: PMC2646831.
- Mukherjee A, Soyal SM, Fernandez-Valdivia R, DeMayo FJ, Lydon JP. (2007). Targeting reverse tetracycline-dependent transactivator to murine mammary epithelial cells that express the progesterone receptor. Genesis. 2007 Oct;45(10):639-46. PubMed PMID: 17941046.
- Hiremath M, Lydon JP, Cowin P. (2007). The pattern of beta-catenin responsiveness within the mammary gland is regulated by progesterone receptor. Development. Oct;134(20):3703-12. Epub 2007 Sep 19. PubMed PMID: 17881490.
- Mukherjee A, Soyal SM, Wheeler DA, Fernandez-Valdivia R, Nguyen J, DeMayo FJ and Lydon JP. (2006). Targeting iCre expression to murine progesterone receptor cell-lineages using bacterial artificial chromosome transgenesis. Genesis. Dec; 44(12):601-10.
- Lee K, Jeong J, Kwak I, Yu CT, Lanske B, Soegiarto DW, Toftgard R, Tsai MJ, Tsai S, Lydon JP and DeMayo FJ. (2006). Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus. Nature Genetics. Oct; 8(10):1204-9.