Sandra Z. Haslam, Ph.D.

Professor of Physiology; Director, Breast Cancer and the Environment Research Center.

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 Center.

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. The Center´s research focuses on testing this hypothesis in animal models. We will determine how environmental influences such as exposure to environmental estrogens and adolescent obesity affect the timing of sexual maturation, mammary gland development and the risk of developing breast 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.

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.

Representative Publications:

Santos SJ, Aupperlee MD, Xie J, Durairaj S, Miksicek R, Conrad SE, Leipprandt JR, Tan YS, Schwartz RC, Haslam SZ. Progesterone receptor A-regulated gene expression in mammary organoid cultures. J Steroid Biochem Mol Biol. 2009 Jul;115(3-5):161-72. Epub 2009 Apr 19.

Yang C, Tan YS, Harkema JR, Haslam SZ. Differential effects of peripubertal exposure to perfluorooctanoic acid on mammary gland development in C57Bl/6 and Balb/c mouse strains. Reprod Toxicol. 2009 Jun;27(3-4):299-306. Epub 2008 Nov 1.

Aupperlee MD, Drolet AA, Durairaj S, Wang W, Schwartz RC, Haslam SZ. Strain-specific differences in the mechanisms of progesterone regulation of murine mammary gland development. Endocrinology. 2009 Mar;150(3):1485-94.

Haslam SZ, Drolet A, Smith K, Tan M, Aupperlee M. Progestin-regulated luminal cell and myoepithelial cell-specific responses in mammary organoid culture. Endocrinology. 2008 May;149(5):2098-107.

Kariagina A, Aupperlee MD, Haslam SZ. Progesterone receptor isoform functions in normal breast development and breast cancer. Crit Rev Eukaryot Gene Expr. 2008;18(1):11-33. Review.

Xie JW, Haslam SZ. Extracellular matrix, Rac1 signaling, and estrogen-induced proliferation in MCF-7 breast cancer cells. Breast Cancer Res Treat. 2008 Jul;110(2):257-68. Epub 2007 Sep 13.

Kariagina A, Aupperlee MD, Haslam SZ. Progesterone receptor isoforms and proliferation in the rat mammary gland during development. Endocrinology. 2007 Jun;148(6):2723-36. Epub 2007 Mar 1.

Other Publications
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