Professor of Physiology , Interim Director, MSU Cancer Center, Director, Research Program in Breast Cancer Research; Chairperson, Cancer Etiology Task Force, College of Human Medicine.
Professor of Physiology , Interim Director, MSU Cancer Center, Director, Research
Program in Breast Cancer Research; Chairperson, Cancer Etiology Task Force,
College of Human Medicine.
Cell Biology, tumor biology, endocrinology; hormone-mediated growth control of normal and cancerous breast cells; epithelial-stromal cell interactions and extracellular matrix molecules as modulators of hormone- and growth factor-mediated growth control
Growth of normal mammary gland is critically dependent upon the ovarian hormones, estrogen and progesterone and various growth factors. 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 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 the cellular distribution of growth factors such as EGF, TGF-a, TGF-b, bFGF, EGF-I,II and ECM components such as collagen I, IV, laminin, fibronectin and tenascin in relation to the acquisition of responsiveness to estrogen and progesterone. One objective is to alter hormonal responsiveness in vivo by surgically manipulating the stromal environment, thus creating unique epithelial-stromal tissue recombinants which exhibit novel hormone responses. Using cell culture systems, epithelial cells and stromal cells can be physically separated from one another and further dissected into their biochemical and molecular components. Reconstitution can be experimentally manipulated to identify the specific components of the cell-cell interactions. 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:
Book Chapters/Reviews:
J.L. Fendrick, A.M. Raafat, S.Z. Haslam Mammary gland growth and development from the postnatal period to menopause: ovarian steroid receptor ontogeny and regulation in the mouse. J. Mammary Gland Biology and Neoplasia Vol 3: 7-22 (1998).
T.L. Woodward, J-W. Xie, S.Z. Haslam The role of mammary stroma in modulating the proliferative response to ovarian hormones in the normal mammary gland. J. Mammary Gland Biology and Neoplasia Vol3: 117-131 (1998).
Articles:
L.J. Hofsth, A.M. Raafat, J.R. Osuch, D.R. Pathak, C. Slomski, S.Z. Haslam Effects of hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate on normal breast tissue in postmenopausal women. (Submitted)
A.M. Raafat, L.J. Hofseth, S.J. Li, J.M. Bennett, S.Z. Haslam A mouse model to study the effects of hormone replacement therapy on normal mammary during menopause: enhanced proliferative response to estrogen in late postmenopausal mice. (In Press, Endocrinology)
C-Y. Hsieh, R.C. Santell, S.Z. Haslam, W. G. Helferich Estrogenic effects of genestein on growth of estrogen receptor positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Research 58: 3833-3838 (1998).
D.P. Ankrapp, J.M. Bennett, and S.Z. Haslam. The role of epidermal growth factor in the acquisition of ovarian steroid hormone responsiveness in the normal mouse mammary gland. J. Cell. Physiol. 174:251-260 (1998).
J-W. Xie and S.Z. Haslam. Extracellular matrix regulates ovarian hormone-dependent proliferation of mouse mammary epithelial cells. Endocrinology 138: 2466-73 (1997)
Other Publications
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