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Judith Weisz
Title Professor
Institution College of Medicine
Department Obstetrics and Gynecology
Division Obstetric/Gynecology
Address 500 University Drive Hershey PA 17033
Mailbox: H103
Telephone 7175318142
Email
Background
PREFERRED TITLE/ROLE:

Professor of Obstetrics and Gynecology, Division Cheif

SECONDARY APPOINTMENT(S)/ INSTITUTE(S)/ CENTER(S):

The Huck Institute of the Life Sciences

GRADUATE PROGRAM AFFILIATIONS:

Genetics, Nueroscience

EDUCATION:

M.B. B.Chir., Cambridge University and The London Hospital, England
Specialty Training, Mount Sinai Hospital; Worcester Foundation for Experimental Biology; Endocrinology Reproductive Biology

NARRATIVE:

Hormonal Carcinogenesis: Estrogens and Reactive Oxygen Species

Reactive oxygen species (ROS) are known critical contributors to the process of carcinogenesis from initiation through promotion and, possibly, also dissemination by metastases. Environmental chemicals and dietary constituents have been generally considered to be the major sources of potentially carcinogenic ROS and the causes of cellular oxidative stress. However, there is growing body of evidence that hormonal estrogens may also become a source of ROS, and that the mechanism involved are analogous to P450-mediated metabolic activation responsible for the generation of ROS from xenobiotics. The potentially carcinogenic products of estrogens identified are the quinone derivatives of catechol-estrogens, that are the products aromatic hydroxylation of estrone and estradiol, and ROS produced in the course of redox cycling between quinone- and catecholestrogens. Interest in this pathway of metabolic activation of estrogens has been heightened by evidence that estrogens' role in carcinogenesis suggested by epidemiological studies can not be fully accounted for by their estrogen receptor mediated actions as mitogens.

Our previous studies focused on characterizing the pathways of catecholestrogen formation, in particular, in the hamster kidney model of estrogen induced renal cancer. We are now concentrating on establishing the relevance of the findings obtained in these and other basic biochemical and molecular biological studies to the human, in particular, the genesis of breast cancer. We are using a multidisciplinary approach encompassing molecular biology, biochemistry and cytochemistry. Thus far we have demonstrated normal human mammary ductal epithelial cells (that are the cells of origin of most breast cancer), express virtually all of the genes encoding the known enzymes required for the metabolic activation and redox cycling of estrogens. We are in the process of characterizing the regulatory untranslated portion of the transcript for most recently identified member of the P450 superfamily that can catalyze aromatic hydroxylation of estrogens, and then plan to identify and clone the gene for what promises to be a novel form of P450 that can catalyze catecholestrogen formation via a peroxidatic mechanism. This mechanism, first identified in our previous biochemical studies, has characteristics that could make it especially relevant to carcinogenesis since it utilizes as its co-factor organic hydroperoxides known to be generated under conditions of oxidative stress.

We have recently turned our attention to developing a histoculture system appropriate for examining the role of estrogen metabolism in immortalization and transformation of human mammary epithelial cells. We have decided to use histoculture, rather than cell lines for these studies, because in histoculture the three dimensional structure and cellular heterogeneity of the mammary gland is preserved. Hence, it allows for cell-cell interactions, including those between stromal and epithelial cells that are known to play a critical role both in normal hormone action and in carcinogenesis. Once characterized, this system will enable us not only to assess the effect of estrogens and of estrogen metabolism on breast tissue but also the interactions between estrogens and environmental chemicals.
Publications
1. Wang N, Eckert KA, Zomorrodi AR, Xin P, Pan W, Shearer DA, Weisz J, Maranus CD, Clawson GA. Down-regulation of HtrA1 activates the epithelial-mesenchymal transition and ATM DNA damage response pathways. PLoS One. 2012; 7(6):e39446.
  View in: PubMed
 
2. Macneill C, de Guzman G, Sousa GE, Umstead TM, Phelps DS, Floros J, Ahn K, Weisz J. Cyclic changes in the level of the innate immune molecule, surfactant protein-a, and cytokines in vaginal fluid. Am J Reprod Immunol. 2012 Sep; 68(3):244-50.
  View in: PubMed
 
3. Durrani F, Phelps DS, Weisz J, Silveyra P, Hu S, Mikerov AN, Floros J. Gonadal hormones and oxidative stress interaction differentially affects survival of male and female mice after lung Klebsiella pneumoniae infection. Exp Lung Res. 2012 May; 38(4):165-72.
  View in: PubMed
 
4. Weisz J, Shearer DA, Murata E, Patrick SD, Han B, Berg A, Clawson GA. Identification of mammary epithelial cells subject to chronic oxidative stress in mammary epithelium of young women and teenagers living in USA: implication for breast carcinogenesis. Cancer Biol Ther. 2012 Jan 15; 13(2):101-13.
  View in: PubMed
 
5. Mikse OR, Blake DC, Jones NR, Sun YW, Amin S, Gallagher CJ, Lazarus P, Weisz J, Herzog CR. FOXO3 encodes a carcinogen-activated transcription factor frequently deleted in early-stage lung adenocarcinoma. Cancer Res. 2010 Aug 1; 70(15):6205-15.
  View in: PubMed
 
6. Erin N, Wang N, Xin P, Bui V, Weisz J, Barkan GA, Zhao W, Shearer D, Clawson GA. Altered gene expression in breast cancer liver metastases. Int J Cancer. 2009 Apr 1; 124(7):1503-16.
  View in: PubMed
 
7. Pavlovic J, Floros J, Phelps DS, Wigdahl B, Welsh P, Weisz J, Shearer DA, Leure du Pree A, Myers R, Howett MK. Differentiation of xenografted human fetal lung parenchyma. Early Hum Dev. 2008 Mar; 84(3):181-93.
  View in: PubMed
 
8. MacNeill C, Umstead TM, Phelps DS, Lin Z, Floros J, Shearer DA, Weisz J. Surfactant protein A, an innate immune factor, is expressed in the vaginal mucosa and is present in vaginal lavage fluid. Immunology. 2004 Jan; 111(1):91-9.
  View in: PubMed
 
9. Triano EA, Slusher LB, Atkins TA, Beneski JT, Gestl SA, Zolfaghari R, Polavarapu R, Frauenhoffer E, Weisz J. Class I alcohol dehydrogenase is highly expressed in normal human mammary epithelium but not in invasive breast cancer: implications for breast carcinogenesis. Cancer Res. 2003 Jun 15; 63(12):3092-100.
  View in: PubMed
 
10. MacNeill C, Weisz J, Carey JC. Clinical resistance of recurrent Candida albicans vulvovaginitis to fluconazole in the presence and absence of in vitro resistance. J Reprod Med. 2003 Feb; 48(2):63-8.
  View in: PubMed
 
11. Gestl SA, Green MD, Shearer DA, Frauenhoffer E, Tephly TR, Weisz J. Expression of UGT2B7, a UDP-glucuronosyltransferase implicated in the metabolism of 4-hydroxyestrone and all-trans retinoic acid, in normal human breast parenchyma and in invasive and in situ breast cancers. Am J Pathol. 2002 Apr; 160(4):1467-79.
  View in: PubMed
 
12. Cain JM, Zaino R, Shearer D, Bennett RA, Olt G, Weisz J. Expression of a retinol dehydrogenase (hRoDH-4), a member of the retinol/steroid dehydrogenase family implicated in retinoic acid biosynthesis, in normal and neoplastic endometria. Am J Obstet Gynecol. 2002 Apr; 186(4):675-83.
  View in: PubMed
 
13. Weisz J, Fritz-Wolz G, Gestl S, Clawson GA, Creveling CR, Liehr JG, Dabbs D. Nuclear localization of catechol-O-methyltransferase in neoplastic and nonneoplastic mammary epithelial cells. Am J Pathol. 2000 Jun; 156(6):1841-8.
  View in: PubMed
 
14. Weisz J, Bui QD, Roy D, Liehr JG. Elevated 4-hydroxylation of estradiol by hamster kidney microsomes: a potential pathway of metabolic activation of estrogens. Endocrinology. 1992 Aug; 131(2):655-61.
  View in: PubMed
 
15. Bui QD, Weisz J, Wrighton SA. Hepatic catecholestrogen synthases: differential effect of sex, inducers of cytochromes P-450 and of antibody to the glucocorticoid inducible cytochrome P-450 on NADPH-dependent estrogen-2-hydroxylase and on organic hydroperoxide-dependent estrogen-2/4-hydroxylase activity of rat hepatic microsomes. J Steroid Biochem Mol Biol. 1990 Oct; 37(2):285-93.
  View in: PubMed
 
16. Liehr JG, Roy D, Ari-Ulubelen A, Bui QD, Weisz J, Strobel HW. Effect of chronic estrogen treatment of Syrian hamsters on microsomal enzymes mediating formation of catecholestrogens and their redox cycling: implications for carcinogenesis. J Steroid Biochem. 1990 Apr; 35(5):555-60.
  View in: PubMed
 
17. Bui QD, Weisz J. Monooxygenase mediating catecholestrogen formation by rat anterior pituitary is an estrogen-4-hydroxylase. Endocrinology. 1989 Feb; 124(2):1085-7.
  View in: PubMed
 
18. Hersey RM, Nazir MA, Whitney KD, Klein RM, Sale RD, Hinton DA, Weisz J, Gattone VH. Atrial natriuretic peptide in heart and specific binding in organs from fetal and newborn rats. Cell Biochem Funct. 1989 Jan; 7(1):35-41.
  View in: PubMed
 
19. Salisbury R, Reed J, Ward IL, Weisz J. Plasma luteinizing hormone levels in normal and prenatally stressed male and female rat fetuses and their mothers. Biol Reprod. 1989 Jan; 40(1):111-7.
  View in: PubMed
 
20. Bui Q, Weisz J. Identification of microsomal, organic hydroperoxide-dependent catechol estrogen formation: comparison with NADPH-dependent mechanism. Pharmacology. 1988; 36(5):356-64.
  View in: PubMed
 
21. Levin M, Weisz J, Bui QD, Santen RJ. Peroxidatic catecholestrogen production by human breast cancer tissue in vitro. J Steroid Biochem. 1987 Nov; 28(5):513-20.
  View in: PubMed
 
 
Keyword
Last Name
Institution
    
 
 
 
Keywords   
Breast
Breast Neoplasms
Epithelial Cells
Mammary Glands, Human
Tretinoin
See all (166) keywords
Co-Authors  
Clawson, Gary
Floros, Joanna
Frauenhoffer, Elizabeth
Macneill, Colin
Phelps, David
See all (16) people
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