Darryl Hadsell, Ph.D.
Pediatrics and Molecular and Cellular Biology
Ph.D. - Penn State University, State College, PA
Postdoctoral - Baylor College of Medicine, Houston, TX
Molecular Pathways in the Regulation of Lactation
Lactation is the ultimate reproductive investment by female mammals to ensure the survival of healthy offspring. The quantity of milk produce is controlled by three separate, but interacting processes; 1) mammary cell turnover, 2) mammary cell biosynthetic activity, and 3) Endocrine and whole body metabolic activity.
The regulation of mammary cell turnover involves an interplay between signaling pathways that regulate cell cycle progression, cell differentiation and cell death. My laboratory uses state-of-the-art immunohistochemical and molecular biological techniques to analyze the relationships between signaling pathways and in-vivo developmental processes that occur in the lactating mammary gland. Transgenic and knockout mouse models are used to determine the impact of perturbing specific signaling pathways on the regulation of postpartum mammary cell turnover.
Our work on IGF-I action suggests that variation signaling pathway use by the IGF-I receptor (Igf1r) occurs at different developmental stages. During lactation IGF-I relies on cell survival pathways to inhibit mammary cell apoptosis while during earlier stages of development IGF-I action occurs through proliferative pathways. Crosses between Igf1r knockout mice and transgenic mice which overexpress downstream signaling proteins will serve to analyzed in vivo mechanisms of IGF-I action during early mammary gland development. The impact of overexpression of IGF-I and of the downstream Igf1r signaling proteins on lactation and mammary cell apoptosis is being analyzed both during normal lactation and during prolonged lactation. Lastly, studies are determining the importance of myc/max/mad family proteins in the regulation of early postpartum mammary cell proliferation.
Hadsell DL, Torres D, George J, Capuco AV, and Fiorotto ML. Changes in secretory cell turnover, and mitochondrial oxidative damage in the mouse mammary gland during a single prolonged lactation cycle suggest the possibility of accelerated cellular aging. Exp. Gerontology (in press) 2006.
Divisova J, Kuiatse I, Lazard Z, Weiss H, Vreeland F, Hadsell DL, Schiff R, Osborne CK, Lee AV. The growth hormone receptor antagonist pegvisomant blocks both mammary gland development and MCF-7 breast cancer xenograft growth. Breast Cancer Res. (in press) 2006.
Hadsell DL, Torres DT, Lawrence NA, George J, Parlow AF, Lee AV, Fiorotto ML. Overexpression of des(1-3) insulin-like growth factor 1 in the mammary glands of transgenic mice delays the loss of milk production with prolonged lactation. Biol Reprod. 73(6):1116-1125, 2005.
Carboni JM, Lee AV, Hadsell DL, Rowley BR, Lee FY, Bol DK, Camuso AE, Gottardis M, Greer AF, Ho CP, Hurlburt W, Li A, Saulnier M, Velaparthi U, Wang C, Wen ML, Westhouse RA, Wittman M, Zimmermann K, Rupnow BA, Wong TW. Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor. Cancer Res. 65(9):3781-3787, 2005.
Hadsell DL. Genetic manipulation of mammary gland development and lactation. Adv Exp Med Biol. 554:229-251, 2004.
Lee AV, Taylor ST, Greenall J, Mills JD, Tonge DW, Zhang P, George J, Fiorotto ML, Hadsell DL. Rapid induction of IGF-IR signaling in normal and tumor tissue following intravenous injection of IGF-I in mice. Horm Metab Res. 35(11-12):651-655, 2003.
Hadsell DL, Bonnette S, George J, Torres D, Klementidis Y, Gao S, Haney PM, Summy-Long J, Soloff MS, Parlow AF, Sirito M, Sawadogo M. Diminished milk synthesis in upstream stimulatory factor 2 null mice is associated with decreased circulating oxytocin and decreased mammary gland expression of eukaryotic initiation factors 4E and 4G. Mol Endocrinol. 17(11):2251-2267, 2003.
Oesterreich S, Deng W, Jiang S, Cui X, Ivanova M, Schiff R, Kang K, Hadsell DL, Behrens J, Lee AV. Estrogen-mediated down-regulation of E-cadherin in breast cancer cells. Cancer Res. 63(17):5203-5208, 2003.
Lee AV, Zhang P, Ivanova M, Bonnette S, Oesterreich S, Rosen JM, Grimm S, Hovey RC, Vonderhaar BK, Kahn CR, Torres D, George J, Mohsin S, Allred DC, Hadsell DL. Developmental and hormonal signals dramatically alter the localization and abundance of insulin receptor substrate proteins in the mammary gland. Endocrinology. 144(6):2683-2694, 2003.
Chakravarty G, Hadsell D, Buitrago W, Settleman J, Rosen JM. p190-B RhoGAP regulates mammary ductal morphogenesis. Mol Endocrinol. 17(6):1054-1065, 2003.
Seagroves TN, Hadsell D, McManaman J, Palmer C, Liao D, McNulty W, Welm B, Wagner KU, Neville M, Johnson RS. HIF1alpha is a critical regulator of secretory differentiation and activation, but not vascular expansion, in the mouse mammary gland. Development. 130(8):1713-1724, 2003.
Hovey RC, Harris J, Hadsell DL, Lee AV, Ormandy CJ, Vonderhaar BK. Local insulin-like growth factor-II mediates prolactin-induced mammary gland development. Mol Endocrinol. 17(3):460-471, 2003.
Hadsell DL. The insulin-like growth factor system in normal mammary gland function. Breast Dis. 17:3-14, 2003.
Lee AV, Schiff R, Cui X, Sachdev D, Yee D, Gilmore AP, Streuli CH, Oesterreich S, Hadsell DL. New mechanisms of signal transduction inhibitor action: receptor tyrosine kinase down-regulation and blockade of signal transactivation. Clin Cancer Res. 9(1 Pt 2):516S-23S, 2003.
Hadsell, DL, Bonnette SG, Klemintidis Y, George J, Torres D1, Gao S, Haney P, and Sawadogo M. Targeted mutation of the upstream stimulatory factor 2 (Usf2) gene impairs lactation. Genes & Dev:, 2002.
Hadsell DL, Bonnette SG, Lee AV. Genetic manipulation of the IGF-I axis to regulate mammary gland development and function. J. Dairy Sci., 2001.
Bonnette SG. and Hadsell DL. Targeted disruption of the insulin like growth factor I receptor gene decreases cellular proliferation in mammary terminal end buds (TEB). Endocrinology 142(11):4937-4945, 2001.
Hadsell DL, and Alexeenko T, Klemintidis YK, Torres D, and Lee AV. Inability of overexpressed des(1-3)hIGF-I to inhibit forced mammary gland involution is associated with decreased abundance of IGF signaling molecules. Endocrinology 142(4):1479-1488, 2001.
Hadsell DL, Murphy CL, Reese N, Laucirica R, Bonnette SG, and Rosen J. Cooperative interaction between mutant p53 and des(1-3)IGF-I accelerates mammary tumorigenesis. Oncogene 19(7):889-898, 2000.