Biomedical subjects

Sandra Z Haslam

Publications and source records attributed to Sandra Z Haslam.

11 recordsLinked to original sources

PubMed2005

Progesterone receptor isoforms A and B: temporal and spatial differences in expression during murine mammary gland development.

Progesterone is a potent mitogen in the mammary gland. Based on studies using cells and animals engineered to express progesterone receptor (PR) isoforms A or B, PRA and PRB are believed to have different functions. Using an immunohistochemical approach with antibodies specific for PRA only or PRB only, we show that PRA and PRB expression in mammary epithelial cells is temporally and spatially separated during normal mammary gland development in the BALB/c mouse. In the virgin mammary gland when ductal development is active, the only PR protein isoform expressed was PRA. PRA levels were significantly lower during pregnancy, suggesting a minor role at this stage of development. PRB was abundantly expressed only during pregnancy, during alveologenesis. PRA and PRB colocalization occurred in only a small percentage of cells. During pregnancy there was extensive colocalization of PRB with 5-bromo-2'-deoxyuridine (BrdU) and cyclin D1; 95% of BrdU-positive cells and 83% of cyclin D1-positive cells expressed PRB. No colocalization of PRA with either BrdU or cyclin D1 was observed at pregnancy. In the virgin gland, PRA colocalization with BrdU or cyclin D1 was low; only 27% of BrdU-positive cells and 4% of cyclin D1-positive cells expressed PRA. The implication of these findings is that different actions of progesterone are mediated in PRB positive vs. PRA-positive cells in vivo. The spatial and temporal separation of PR isoform expression in mouse mammary gland provides a unique opportunity to determine the specific functions of PRA vs. PRB in vivo.

Animals↗

PubMed2004

Estrogen increases brain expression of the mRNA encoding transthyretin, an amyloid beta scavenger protein.

Estrogen replacement therapy in postmenopausal women is associated with a reduced risk of Alzheimer's Disease (AD). The multiple mechanisms by which estrogen protects against AD are still unknown. To conduct a broad screen for estrogen-regulated AD-related genes in the brain, we used cDNA array assays of brain mRNA samples from ovariectomized (ovx) adult female mice treated with either 17beta-estradiol or vehicle at 1 or 5 weeks post-ovx. The gene encoding transthyretin (TTR), which has been reported to scavenge amyloid beta peptides and reduce amyloid plaque formation, is increased by estradiol treatment at both 1 and 5 weeks post-ovx. Northern blot analyses and RNase protection assays performed on whole brain samples obtained from estradiol- or vehicle-treated mice confirmed the cDNA array assays showing a significant increase in TTR mRNA with estradiol treatment. Qualitative in situ hybridization or immunocytochemistry performed on brain sections demonstrated that TTR mRNA is expressed only in choroid plexus and leptomeninges, and that both estrogen receptor proteins, alpha and beta, are present in choroid plexus cells. These novel findings suggest that estrogen may reduce the risk of AD by acting on choroid plexus cells to increase TTR gene expression, leading to enhanced sequestration and reduced aggregation of amyloid beta peptides.

Alzheimer Disease↗

PubMed2003

Host microenvironment in breast cancer development: epithelial-cell-stromal-cell interactions and steroid hormone action in normal and cancerous mammary gland.

Mammary epithelial cells comprise the functional component of the normal gland and are the major target for carcinogenesis in mammary cancer. However, the stromal compartment of the normal gland and of tumors plays an important role in directing proliferative and functional changes in the epithelium. In vivo and in vitro studies of the murine mammary gland have provided insights into novel stroma-dependent mechanisms by which estrogen and progesterone action in the epithelium can be modulated by hepatocyte growth factor (HGF) and the extracellular matrix proteins, collagen type I, fibronectin and laminin. In vitro and in vivo studies of estrogen receptor positive, estrogen-responsive human breast cancer cells have also demonstrated that estrogen responsiveness of tumor cells can also be modulated by extracellular matrix proteins, collagen type I and laminin.

Animals↗

PubMed2003

Breast cancer among young African-American women: a summary of data and literature and of issues discussed during the Summit Meeting on Breast Cancer Among African American Women, Washington, DC, September 8-10, 2000.

BACKGROUND: African-American women younger than age 45 years have a higher risk of incidence and mortality due to breast cancer than other women. The reason for this disparity in risk is not well understood. METHODS: This review summarizes the literature on the topic of breast cancer in young women and presents a summary of a discussion on this topic during a national forum on breast cancer among African-American women. RESULTS: The occurrence of breast cancer among African-American women younger than the age of 45 years has not been well studied. There is a clear and long-term pattern of higher incidence and mortality and poorer survival in this population subgroup. CONCLUSION: Research is needed to understand the reasons for these disparities and to reduce or eliminate them. Studies focused on hormonal factors, genetic factors, diet and obesity, and timely access to state-of-the-art prevention, information, screening, diagnosis, and treatment are likely to produce important new knowledge in this area.

Adult↗

PubMed2002

Normal mammary gland morphology in pubertal female mice following in utero and lactational exposure to genistein at levels comparable to human dietary exposure.

The objective of the study was to determine the effect of in utero and lactational exposure to genistein (0, 0.1, 0.5, 2.5 and 10 mg/kg/day) on mammary gland morphology in female B6D2F1 mice at levels comparable to or greater than human exposures. The effect of diethylstilbestrol (DES; 0, 0.1, 1, 10 microg/kg/day) on the mammary gland was also examined as a positive estrogenic control. Pregnant females were treated by daily gavage from gestational day 12 to postnatal day (PND) 20. Female offspring were weaned on PND21 and mammary gland whole mounts were examined for growth (length and area of the epithelial tree), proliferation (number of terminal end buds (TEBs)), and differentiation (density of alveolar buds (ABs)) on PND49. The highest dose of DES induced a significant increase in mammary gland growth (P<0.05) and also decreased the number of TEBs (P<0.06). The density of ABs was not significantly affected by DES. By contrast to DES, genistein had no effect on mammary gland morphology at any dose. These results suggest that in utero and lactational exposure to genistein at levels comparable to or greater than human exposures do not adversely affect mammary gland development in pubertal female B6D2F1 mice.

Animals↗

PubMed2002

Postmenopausal hormone replacement therapy: effects on normal mammary gland in humans and in a mouse postmenopausal model.

Endogenous estrogen exposure has long been implicated in the causation of breast cancer through a mechanism of epithelial cell proliferation. Whether estrogen, progesterone, or both exhibit mitogenic activity and promote carcinogenesis in the human breast has been the subject of considerable debate. The purpose of this review article is to examine the evidence for the effects of hormone replacement therapy in its various forms on the biology of the postmenopausal breast both in humans and in an animal model, and to identify the gaps in knowledge that research will need to address to further understand this complex issue.

Animals↗

PubMed2002

Estrogen mediates mammary epithelial cell proliferation in serum-free culture indirectly via mammary stroma-derived hepatocyte growth factor.

Epithelial-stromal cell interactions are important for normal development and function of the mouse mammary gland. The steroid hormone estrogen is required for epithelial cell proliferation and ductal development in vivo. Recent studies of estrogen receptor alpha knockout mice indicate that estrogen-induced proliferation is dependent upon the presence of estrogen receptor in mammary stromal cells, but not in epithelial cells. The purpose of the present study was to identify the underlying mechanism of estrogen-dependent stroma-derived effects on mammary epithelium. We have developed a minimally supplemented serum-free medium, collagen gel primary mammary coculture system to address the issue of stroma-derived, estrogen-dependent effects on epithelial cell proliferation. Conditioned medium from mammary fibroblasts or coculture with mammary fibroblasts caused increased epithelial cell proliferation and produced tubular/ductal morphology. Hepatocyte growth factor (HGF) was identified as the mediator of this effect, as the proliferative activity in fibroblast-conditioned medium was completely abolished by neutralizing antibody to HGF, whereas neutralizing antibodies to either epidermal growth factor or IGF-I had no effect. Treatment of mammary fibroblasts with estrogen increased the production of HGF. From these results we conclude that estrogen may indirectly mediate mammary epithelial cell proliferation via the regulation of HGF in mammary stromal cells and that HGF plays a crucial role in estrogen-induced proliferation in vivo.

Animals↗

PubMed2002

Hepatocyte growth factor is required for progestin-induced epithelial cell proliferation and alveolar-like morphogenesis in serum-free culture of normal mammary epithelial cells.

The steroid hormones, estrogen and progesterone, are required for mammary epithelial cell proliferation and alveolar morphogenesis in vivo. We have developed a minimally supplemented, serum-free medium, collagen gel primary mammary culture system to determine the mechanism of progestin-induced proliferation and alveolar morphogenesis. In epithelial cells cultured alone, treatment with progestin (R5020) alone produced a lumen within the epithelial organoids, but did not stimulate epithelial cell proliferation. The formation of lumens was associated with increased apoptosis, targeted within the organoids. We have previously reported that in our culture system hepatocyte growth factor (HGF) increases epithelial cell proliferation and induces a tubulo-ductal morphological response. In the present report we show that treatment with HGF and progestin (R5020) further increases epithelial proliferation above that with HGF alone and also produces an alveolar-like morphology similar to that observed in vivo in response to progestin treatment. To the best of our knowledge this is the first in vitro demonstration of both progestin-induced proliferation and alveolar-like morphogenesis of normal nonpregnant mouse mammary epithelial cells in vitro. These results suggest that HGF may play a crucial role in progestin-induced proliferation and morphogenesis in vivo.

Animals↗

PubMedDate not supplied

Introduction.

Explore the source record for details and available documents.

Aged↗

PubMedDate not supplied

Progestins and breast cancer.

Progesterone (P) regulates proliferation and differentiation in the normal mammary gland in mouse, rat and human. Progesterone has also been implicated in the etiology and pathogenesis of human breast cancer. The focus of this review is on recent advances in understanding the role of the progesterone receptor (PR) and functional significance of PR isoforms, PRA and PRB, in the normal mammary gland and in mammary cancer in mouse, rat and human.

Animals↗

PubMedDate not supplied

Experimental mouse model of hormonal therapy effects on the postmenopausal mammary gland.

Menopausal hormone therapy, in particular estrogen plus progestin therapy, has been associated with increased breast cancer risk. In order to understand the basis for increased breast cancer risk, more information is needed about the effects of menopausal hormone therapies on the breast. In this review we describe studies carried out in a mouse model of early vs. late postmenopausal states. We investigated the effects of 1) estrogen alone, 2) combined continuous estrogen + progestin, 3) systemically vs. locally administered estrogen and progestin, and 4) the effect of pregnancy on the response to hormonal therapies. We analysed the effects on mammary gland morphology and proliferation. Estrogen therapy started in late postmenopause caused a greater proliferative response than when started in early postmenopause. In parous, late postmenopausal mice the greater proliferative response to estrogen was not observed. Overall, the greatest proliferative response was observed with combined continuous estrogen + progestin hormone therapy and did not differ significantly in early vs. late nulliparous or parous postmenopausal mice. Both estrogen and progestin were found to act directly on the mammary gland rather than through systemically mediated effects. The possible implications of these findings for menopausal hormone therapy in women and breast cancer risk are discussed.

Animals↗