Sandra Haslam, Ph.D.
Areas of Research Interest [PDF]
I.Endocrinology of normal breast growth and differentiation; steroid hormone- and growth factor-mediated growth control of normal breast cells.
Postnatal development of normal mammary gland from puberty to menopause is critically dependent upon two nuclear steroid hormones, estrogen and progesterone, a number of peptide hormones, and various growth factors. In the recent past there has been extensive focus on the role of estrogen as a growth regulator of normal breast tissue and breast cancer. However, progesterone is also a potent breast mitogen and recent epidemiological studies suggest that progesterone may play a greater role than estrogen in breast cancer. For this reason we are currently focused on understanding the molecular mechanism of action of progesterone in the normal mammary gland, using the mouse and rat mammary gland as model systems. Progesterone action is mediated through binding to the progesterone receptor. The progesterone receptor consists of two isoforms, PRA and PRB, which are expressed from a single gene in both humans and rodents. The two isoforms are believed to be functionally distinct based upon transgenic overexpression or gene deletion studies. However, their normal functions in vivo have not been identified. We are currently studying progesterone isoform function in vivo in mice at different developmental stages and known to have different functional responses to progesterone and in vitro in a novel primary culture model that recapitulates in vivo response to progesterone.
II. Breast Cancer and the Environment Research Program.
In humans, early onset of menstruation and late menopause are associated with increased breast cancer risk. One hypothesis to explain this observation is that early onset of menses and late menopause increase lifetime exposure of the breast to the mitogenic effects of progesterone. Our program’s research focuses on testing this hypothesis in animal models. We will determine how environmental influences such dietary factors and adolescent obesity as well as chemical exposures affect the timing of sexual maturation, mammary gland development and the risk of developing breast cancer later in life, i.e. adulthood, after exposure to known carcinogens. A specific focus of these studies is the integration of progesterone receptor function and mechanism of action into understanding pubertal vs. adult breast development and breast cancer risk. We are also interested in determining the contribution of inflammatory processes to hormonal and environmental exposure effects on the development of the normal mammary gland and mammary cancer.
III. The role epithelial-stromal cell interactions and extracellular matrix molecules as modulators of hormone- and growth factor-mediated growth control in normal breast development and breast cancer.
The mammary gland is also unique in that most morphologic changes and tissue specific differentiation take place postnatally and require specific, appropriate epithelial-stromal cell interactions. Two mechanisms have been proposed to describe the molecular mechanisms underlying epithelial-stromal cell interactions: 1) by the production of growth factors/growth inhibitors which behave in paracrine ways, and/or 2) by modifying the composition of the extracellular matrix (ECM). The specific composition of the ECM can influence the stability and local concentration of growth factors/inhibitors. Estrogen and progesterone may also alter the composition of the ECM and/or the production of growth factors/inhibitors. The resulting net bioavailability of the various factors would determine the relative proliferative activity in various mammary cell types in response to hormones and growth factors and growth inhibitors at different developmental stages and in breast cancer. We are currently investigating how epithelial-stromal cell interactions modulate proliferative responses of the normal and cancerous breast to estrogen and progesterone and growth factors/growth inhibitors. Using in vivo and in vitro approaches we are examining how stroma-derived growth factors such as HGF, EGF, IGF and ECM components such as collagen I, IV, laminin, and fibronectin can modulate responsiveness to estrogen and progesterone. With the development of breast cancer, a significant percentage of human tumors still exhibit some form of growth regulation by hormones and growth factors. The majority of tumors however, are no longer responsive to growth regulation and are classed as hormone-independent. The long term goal is the detailed analysis of the molecular mechanisms underlying epithelial-stromal cell interactions which result in the transition from a hormonally non-responsive to a responsive state and the development of new therapeutic strategies for the treatment of breast cancer.
Aupperlee MD, Zhao Y, Tan YS, Leipprandt JR, Bennett J, Haslam SZ, Schwartz RC, Epidermal growth factor receptor (EGFR)-signaling is a key mediator of hormone-induced leukocyte infiltration in the pubertal female mammary gland. Endocrinology. 2014, 155:2301-13.
Zhao Y, Tan YS, Aupperlee MD, Langohr IM, Kirk EL, Troester MA, Schwartz RC, Haslam SZ. Pubertal high fat diet: effects on mammary cancer development. Breast Cancer Res 2013;15(5):R100. PMID:24156623[PubMed - in process]
Kariagina A, Xie J, Langohr IM, Opreanu RC, Basson MD, Haslam SZ. Progesterone stimulates proliferation and promotes cytoplasmic localization of the cell cycle inhibitor p27 in steroid receptor positive breast cancers. Horm Cancer. 2013 Dec;4(6):381-90.
Kariagina A, Xie J, Langohr IM, Opreanu RC, Basson MD, Haslam SZ. Progesterone decreases levels of the adhesion protein E-cadherin and promotes invasiveness of steroid receptor positive breast cancers. Horm Cancer. 2013 Dec;4(6):371-80.
Aupperlee MD, Leipprandt JR, Bennett JM, Schwartz RC, Haslam SZ. Amphiregulin mediates progesterone-induced mammary ductal development during puberty. Breast Cancer Res. 2013 May 25;15(3):R44. [Epub ahead of print]
Mark D. Aupperlee, Yong Zhao, Ying Siow Tana, Jeffrey R. Leipprandt, Jessica Bennett, Sandra Z. Haslam, Richard C. Schwartz (Haslam & Schwartz co-corresponding authors) Epidermal growth factor receptor (EGFR)-signaling is a key mediator of hormone-induced leukocyte infiltration in the pubertal female mammary gland (2014) Endocrinology (In Press)
Meyer G, Leipprandt J, Xie J, Aupperlee MD, Haslam SZ 2012 A potential role o progestin-induced laminin-5/α6-integrin signaling in the formation of sidebranches in the mammary gland. Endocrinology (In Press).
Zhao Y, Tan YS, Strynar MJ, Perez G, Haslam SZ, Yang C. 2012 Perfluorooctanoic acid effects on ovaries mediate its inhibition of peripubertal mammary gland development in Balb/c and C57Bl/6 mice.Reprod Toxicol. 33:563-76.
Prashant Rajbhandari1, Greg Finn, Natalia M. Solodin, Kiran K. Singarapu, Sarata C. Sahu, John L. Markley, Kelley J. Kadunc, Stephanie J. Ellison-Zelski, Anastasia Kariagina, Sandra Z. Haslam , Kun Ping Lu & Elaine T. Alarid. 2012 Regulation of ERα N-terminus conformation and function by peptidyl prolyl isomerase Pin1 Cell Mol Biol 32:445-57.
Nguyen DH, Oketch-Rabah HA, Illa-Bochaca I, Geyer FC, Reis-Filho JS, Mao JH, Ravani SA, Zavadil J, Borowsky AD, Jerry DJ, Dunphy KA, Seo JH, Haslam S, Medina D, Barcellos-Hoff MH. 2011 Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type. Cancer Cell 17:640-51.
Haslam SZ, Schwartz RC 2011 Is there a link between a high-fat diet during puberty and breast cancer risk? Womens Health (Lond Engl). 7(1):1-3.
Kariagina A, Xie JW, Leiprandt JR, Haslam SZ . 2010 Amphiregulin mediates estrogen, progesterone and EGFR signaling in the normal rat mammary gland and in hormone-dependent rat mammary cancers. Hormones & Canc 1:229-44.
Zhang C, Mori M, Gao S, Li A, Hoshino I, Aupperlee MD, Haslam SZ, Xiao H. 2010
Tip30 deletion in MMTV-Neu mice leads to enhanced EGFR signaling and development of estrogen receptor-positive and progesterone receptor-negative mammary tumors. Cancer Res.70(24):10224-33.
Santos SJ, Haslam SZ, Conrad SE 2010. Signal transducer and activator of transcription 5a mediates mammary ductal branching and proliferation in the nulliparous mouse. Endocrinol151(6):2876-85.
Olson LK, Tan Y, Zhao Y, Aupperlee MD, Haslam SZ. 2010 Pubertal exposure to high fat diet causes mouse strain-dependent alterations in mammary gland development and estrogen responsiveness.Int J Obes 34(9):1415-26.
Zhao Y, Tan YS, Haslam SZ, Yang C. 2010 Perfluorooctanoic acid effects on steroid hormone and growth factor levels mediate stimulation of peripubertal mammary gland development in C57Bl/6 mice. Toxicol Sci. 115:214-24.
Santos SJ, Aupperlee MD, Xie J, Durairaj S, Miksicek R, Conrad SE, Leipprandt JR, Tan YS, Schwartz RC,Haslam SZ. 2009 Progesterone receptor A-regulated gene expression in mammary organoid cultures. J Steroid Biochem Mol Biol. Jul;115(3-5):161-72. Epub 2009 Apr 19.
Yang C, Tan YS, Harkema JR, Haslam SZ. 2009 Differential effects of peripubertal exposure to perfluorooctanoic acid on mammary gland development in C57Bl/6 and Balb/c mouse strains. Reprod Toxicol. 27:299-306.
Aupperlee MD, Drolet AA, Durairaj S, Wang W, Schwartz RC, Haslam SZ. 2009 Strain-specific differences in the mechanisms of progesterone regulation of murine mammary gland development. Endocrinology. Mar;150:1485-94.
Hiatt RA, Haslam SZ, Osuch J; Breast Cancer and the Environment Research Centers. 2009 The breast cancer and the environment research centers: transdisciplinary research on the role of the environment in breast cancer etiology.Environ Health Perspect.117:1814-22.
Haslam SZ, Drolet A, Smith K, Tan M, Aupperlee M. 2008 Progestin-regulated luminal cell and myoepithelial cell-specific responses in mammary organoid culture. Endocrinology. 149:2098-107.
Kariagina A, Aupperlee MD, Haslam SZ. 2008 Progesterone receptor isoform functions in normal breast development and breast cancer. Crit Rev Eukaryot Gene Expr.;18:11-33. Review.