Apply to Graduate School | Library | Jobs & Volunteers | Visitor Information | Department Index | News      
Comparative Medicine
Dr. Mark Cline

J. Mark Cline, DVM PhD

Professor of Pathology (Comparative Medicine)
Tel: (336) 716-1564 
Fax: (336) 716-1515
jmcline@wfubmc.edu

  • Assistant Director, Diagnostic Services: Animal Resources Program (all campuses)
  • Board Certification: Diplomate, ACVP: Veterinary Pathology
Education:
  • Undergraduate: North Carolina State University, BS 1982
  • Postgraduate: College of Veterinary Medicine, North Carolina State University, DVM, 1986; PhD 1992  
Interests:
  • Teaching: Veterinary and Comparative Pathology; Tumor Biology
  • Research: Carcinogenesis, Immunohistochemistry, Comparative Pathology, Hormonally Induced Changes in Mammary Gland and Endometrium, Women's Health; Tumor Hypoxia
  • Clinical: Veterinary Diagnostic Pathology 
Current Research: 

Work in my laboratory focuses on histopathologic and immunohistochemical methods for characterization of pre-neoplastic lesions and neoplasms. My work concerns the effect of hormonal therapies (hormone replacement after menopause, oral contraceptives, and others) on breast and uterine cancer risk. This work involves the characterization of regulatory changes and pre-cancerous lesions in the endometrium and mammary gland of macaques receiving the various hormonal therapies. Endpoints in these studies are changes in expression of proliferation markers (for example, Ki-67), estrogen and progesterone receptors, growth factor receptors, markers of cell death (apoptosis), and the development of morphologically detectable preneoplastic changes. Soy isoflavones (phytoestrogens) are also being studied, as a dietary alternative to postmenopausal hormonal replacement therapy. Work to date indicates that hormonal regulation of the breast and endometrium differ in postmenopausal animals, and that the combined estrogen-progestin therapy that prevents endometrial cancer increases proliferation in breast epithelial cells and may therefore increase the risk of breast cancer. Our most recent and exciting results indicate that dietary soy supplementation may decrease estrogen-induced cell proliferation and cancer risk in the breast and uterus. 

Figure 1

FIGURE 1: Breast epithelium stained with an antibody to the proliferation marker Ki67. Brown staining indicates proliferation and an associated increase in cancer risk.

Figure 2

FIGURE 2: Ki67 (proliferation marker) staining of breast and endometrium, in animals given estrogen (E2) or a high-soy diet (Soy) or the combination. These results suggest that dietary soy may decrease breast and uterine cancer risk.
Recent Publications:

Wood CE, Hester JM, Cline JM. Mammary gland development in early pubertal female macaques. Toxicol Pathol. 2007;35(6):793-803.

Shively CA, Wood CE, Register TC, Willard SL, Lees CJ, Chen H, Sitruk-Ware RL, Tsong YY, Cline JM. Hormone therapy effects on social behavior and activity levels of surgically postmenopausal cynomolgus monkeys. Psychoneuroendocrinology. 2007 Sep 1; [Epub ahead of print]

Berquin IM, Min Y, Wu R, Wu J, Perry D, Cline JM, Thomas MJ, Thornburg T, Kulik G, Smith A, Edwards IJ, D'Agostino R, Zhang H, Wu H, Kang JX, Chen YQ. Modulation of prostate cancer genetic risk by omega-3 and omega-6 fatty acids. J Clin Invest. 2007 Jul;117(7):1866-75.

Perry DL, Spedick JM, McCoy TP, Adams MR, Franke AA, Cline JM. Dietary soy protein containing isoflavonoids does not adversely affect the reproductive tract of male cynomolgus macaques (Macaca fascicularis). J Nutr. 2007 Jun;137(6):1390-4.

Trybus J, Bain FT, Fikes JD, Carlson CS, O'Sullivan MG, Jayo MJ, Cline JM. Uterine infarctions in cynomolgus monkeys (Macaca fascicularis). Vet Pathol. 2007 May;44(3):309-13.

Cline JM. Assessing the mammary gland of nonhuman primates: effects of endogenous hormones and exogenous hormonal agents and growth factors. Birth Defects Res B Dev Reprod Toxicol. 2007 Apr;80(2):126-46. Review.

Cline JM. Tibolone: example of qualitative and quantitative assessments of the mammary gland. Birth Defects Res B Dev Reprod Toxicol. 2007 Apr;80(2):147-8.

Wood CE, Chen Z, Cline JM, Miller BE, Burk RD. Characterization and experimental transmission of an oncogenic papillomavirus in female macaques. J Virol. 2007 Jun;81(12):6339-45.

Menon J, Soto-Pantoja DR, Callahan MF, Cline JM, Ferrario CM, Tallant EA, Gallagher PE. Angiotensin-(1-7) inhibits growth of human lung adenocarcinoma xenografts in nude mice through a reduction in cyclooxygenase-2. Cancer Res. 2007 Mar 15;67(6):2809-15.

Sikoski P, Register TC, Lees CJ, Lundeen S, Hutchison J, Brown KH, Cline JM. Effects of two novel selective estrogen receptor modulators, raloxifene, tamoxifen, and ethinyl estradiol on the uterus, vagina and breast in ovariectomized cynomolgus monkeys (Macaca fascicularis). Am J Obstet Gynecol. 2007 Jan;196(1):75.e1-7.

Wood CE, Sitruk-Ware RL, Tsong YY, Register TC, Lees CJ, Cline JM. Effects of estradiol with oral or intravaginal progesterone on risk markers for breast cancer in a postmenopausal monkey model. Menopause. 2007 Jul-Aug;14(4):639-47.

Wood CE, Clarkson TB, Appt SE, Franke AA, Boue SM, Burow ME, McCoy T, Cline JM. Effects of soybean glyceollins and estradiol in postmenopausal female monkeys. Nutr Cancer. 2006;56(1):74-81.

Wood CE, Register TC, Cline JM. Soy isoflavonoid effects on endogenous estrogen metabolism in postmenopausal female monkeys. Carcinogenesis. 2006 Oct 9; [Epub ahead of print]

Appt SE, Kaplan JR, Clarkson TB, Cline JM, Christian PJ, Hoyer PB. Destruction of primordial ovarian follicles in adult cynomolgus macaques after exposure to 4-vinylcyclohexene diepoxide: a nonhuman primate model of the menopausal transition. Fertil Steril. 2006 Oct;86 Suppl 4:1210-6.

Cline JM, Wood CE. Hormonal effects on the mammary gland of postmenopausal nonhuman primates. Breast Dis. 2005-2006;24:59-70. Review.

Remick AK, Wood CE, Cann JA, Gee MK, Feiste EA, Kock ND, Cline JM. Histologic and immunohistochemical characterization of spontaneous pituitary adenomas in fourteen cynomolgus macaques (Macaca fascicularis). Vet Pathol. 2006 Jul;43(4):484-93.

Wood CE, Usborne AL, Starost MF, Tarara RP, Hill LR, Wilkinson LM, Geisinger KR, Feiste EA, Cline JM. Hyperplastic and neoplastic lesions of the mammary gland in macaques. Vet Pathol. 2006 Jul;43(4):471-83.

Wood CE, Register TC, Lees CJ, Chen H, Kimrey S, Mark Cline J. Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys. Breast Cancer Res Treat. 2006 Jul 14; [Epub ahead of print] 

Wood CE, Appt SE, Clarkson TB, Franke AA, Lees CJ, Doerge DR, Cline JM. Effects of High-Dose Soy Isoflavones and Equol on Reproductive Tissues in Female Cynomolgus Monkeys. Biol Reprod. 2006 May 24; [Epub ahead of print]

Stute P, Register TC, Blair RM, Cline JM. Effects of tibolone on estrogen biosynthesis in the mammary tissue of postmenopausal monkeys. Menopause. 2006 Mar-Apr;13(2):232-40.

Wood CE, Kaplan JR, Stute P, Cline JM. Effects of soy on the mammary glands of premenopausal female monkeys. Fertil Steril. 2006 Apr;85 Suppl 1:1179-86.

Wilkinson Iv J, Di X, Schonig K, Buss JL, Kock ND, Cline JM, Saunders TL, Bujard H, Torti SV, Torti FM. Tissue-specific expression of ferritin H regulates cellular iron homeostasis in vivo. Biochem J. 2006 May 1;395(3):501-7.

Wood CE, Register TC, Franke AA, Anthony MS, Cline JM. Dietary soy isoflavones inhibit estrogen effects in the postmenopausal breast. Cancer Res. 2006 Jan 15;66(2):1241-9. 

Conner P, Register TC, Skoog L, Tani E, von Schoultz B, Cline JM. Expression of p53 and markers for apoptosis in breast tissue during long-term hormone therapy in cynomolgus monkeys. Am J Obstet Gynecol. 2005 Jul;193(1):58-63.

Vardy MD, Gardner TR, Cosman F, Scotti RJ, Mikhail MS, Preiss-Bloom AO, Williams JK, Cline JM, Lindsay R. The effects of hormone replacement on the biomechanical properties of the uterosacral and round ligaments in the monkey model. Am J Obstet Gynecol. 2005 May;192(5):1741-51.

Ibdah JA, Perlegas P, Zhao Y, Angdisen J, Borgerink H, Shadoan MK, Wagner JD, Matern D, Rinaldo P, Cline JM. Mice heterozygous for a defect in mitochondrial trifunctional protein develop hepatic steatosis and insulin resistance. Gastroenterology. 2005 May;128(5):1381-90.

Regan KS, Cline JM, Creasy D, Davis B, Foley GL, Lanning L, Latendresse JR, Makris S, Morton D, Rehm S, Stebbins K; STP Ovary Evaluation Working Group. STP position paper: ovarian follicular counting in the assessment of rodent reproductive toxicity. Toxicol Pathol. 2005;33(3):409-12.

Angdisen J, Moore VD, Cline JM, Payne RM, Ibdah JA. Mitochondrial trifunctional protein defects: molecular basis and novel therapeutic approaches. Curr Drug Targets Immune Endocr Metabol Disord. 2005 Mar;5(1):27-40. Review.

Cohen KA, Liu TF, Cline JM, Wagner JD, Hall PD, Frankel AE. Safety evaluation of DT(388)IL3, a diphtheria toxin/interleukin 3 fusion protein, in the cynomolgus monkey. Cancer Immunol Immunother. 2004 Dec 22; [Epub ahead of print]

Stute P, Wood CE, Kaplan JR, Cline JM. Cyclic changes in the mammary gland of cynomolgus macaques. Fertil Steril. 2004 Oct;82 Suppl 3:1160-70.

Cohen K, Liu TF, Cline JM, Wagner J, Hall P, Frankel A. Toxicology and pharmacokinetics of DT(388)IL3, a fusion toxin consisting of a truncated diphtheria toxin (DT(388)) linked to human interleukin 3 (IL3), in cynomolgus monkeys. Leuk Lymphoma. 2004;45(8):1647-1656.

Clarkson TB, Appt SE, Wood CE, Cline JM. Lessons to be learned from animal studies on hormones and the breast. Maturitas. 2004 Sep 24;49(1):79-89.

Clarkson TB, Anthony MS, Cline JM, Lees CJ, Ederveen AG. Multisystem evaluations of the long-term effects of tibolone on postmenopausal monkeys. Maturitas. 2004 Aug 30;48 Suppl 1:24-9.

Shively CA, Register TC, Grant KA, Johnson JL, Cline JM. Effects of social status and moderate alcohol consumption on mammary gland and endometrium of surgically postmenopausal monkeys. Menopause. 2004 Jul-Aug;11(4):389-99.

Wood CE, Register TC, Anthony MS, Kock ND, Cline JM. Breast and uterine effects of soy isoflavones and conjugated equine estrogens in postmenopausal female monkeys. J Clin Endocrinol Metab. 2004 Jul;89(7):3462-8.

Yaksh TL, Horais KA, Tozier N, Rathbun M, Richter P, Rossi S, Grafe M, Tong C, Meschter C, Cline JM, Eisenach J. Intrathecal ketorolac in dogs and rats. Toxicol Sci. 2004 Aug;80(2):322-334.

Wood CE, Cline JM, Anthony MS, Register TC, Kaplan JR. Adrenocortical effects of oral estrogens and soy isoflavones in female monkeys. J Clin Endocrinol Metab. 2004 May;89(5):2319-25.

Cline JM. Neoplasms of the reproductive tract: the role of hormone exposure. ILAR J. 2004;45(2):179-88.

Wood CE, Borgerink H, Register TC, Scott L, Cline JM. Cervical and vaginal epithelial neoplasms in cynomolgus monkeys. Vet Pathol. 2004 Mar;41(2):108-15.

Cline JM, Franke AA, Register TC, Golden DL, Adams MR. Effects of dietary isoflavone aglycones on the reproductive tract of male and female mice. Toxicol Pathol. 2004 Jan-Feb; 32(1): 91-9.

Register TC, Cline JM, Shively CA. Health issues in postmenopausal women who drink. Alcohol Res Health. 2002;26(4):299-307.

Isaksson E, Wang H, Sahlin L, von Schoultz B, Cline JM, von Schoultz E. Effects of long-term HRT and tamoxifen on the expression of progesterone receptors A and B in breast tissue from surgically postmenopausal cynomolgus macaques. Breast Cancer Res Treat. 2003 May;79(2):233-9.

Suparto IH, Williams JK, Cline JM, Anthony MS, Fox JL. Contrasting effects of two hormone replacement therapies on the cardiovascular and mammary gland outcomes in surgically postmenopausal monkeys. Am J Obstet Gynecol. 2003 May;188(5):1132-40.

Wang H, Isaksson E, Von Schoultz B, Cline JM, Sahlin L. Effect of long-term treatment with steroid hormones or tamoxifen on the progesterone receptor and androgen receptor in the endometrium of ovariectomized cynomolgus macaques. Reprod Biol Endocrinol. 2003 Feb 5;1(1):7.

Goodrich JA, Clarkson TB, Cline JM, Jenkins AJ, Del Signore MJ. Value of the micropig model of menopause in the assessment of benefits and risks of postmenopausal therapies for cardiovascular and reproductive tissues. Fertil Steril. 2003 Mar;79(3 Suppl 1):779-88.

Wang H, Isaksson E, Von Schoultz B, Cline JM, Sahlin L. The effect of long-term treatment with steroid hormones or tamoxifen on oestrogen receptors (alpha and beta) in the endometrium of ovariectomized cynomolgus macaques. J Endocrinol. 2002 Dec; 175(3): 673-81.

Cline JM, Register TC, Clarkson TB. Effects of tibolone and hormone replacement therapy on the breast of cynomolgus monkeys. Menopause. 2002 Nov-Dec;9(6):422-9.

Ramsey MM, Ingram RL, Cashion AB, Ng AH, Cline JM, Parlow AF, Sonntag WE. Growth hormone-deficient dwarf animals are resistant to dimethylbenzanthracine (DMBA)-induced mammary carcinogenesis. Endocrinology. 2002 Oct;143(10):4139-42.

Isaksson E, Wang H, Sahlin L, von Schoultz B, Masironi B, von Schoultz E, Cline JM. Expression of estrogen receptors (alpha, beta) and insulin-like growth factor-I in breast tissue from surgically postmenopausal cynomolgus macaques after long-term treatment with HRT and tamoxifen. Breast. 2002 Aug;11(4):295-300.

Cline JM, Register TC, Clarkson TB. Comparative effects of tibolone and conjugated equine estrogens with and without medroxyprogesterone acetate on the reproductive tract of female cynomolgus monkeys. Menopause. 2002 Jul-Aug;9(4):242-52.

Paramastri YA, Wallace JM, Salleng KJ, Wilkinson LM, Malarkey DE, Cline JM. Intracranial lymphomas in simian retrovirus-positive Macaca fascicularis. Vet Pathol. 2002 May; 39(3): 399-402.

Vidal JD, Register TC, Gupta M, Cline JM. Estrogen replacement therapy induces telomerase RNA expression in the macaque endometrium. Fertil Steril. 2002 Mar;77(3):601-8.

Blair RM, Cline JM, Anthony MS, Clarkson TB. Use of the progestin challenge test in nonhuman primates (Macaca fascicularis). Fertil Steril. 2002 Feb;77(2):387-91.

Hale GE, Hughes CL, Cline JM. Endometrial cancer: hormonal factors, the perimenopausal "window of risk," and isoflavones. J Clin Endocrinol Metab. 2002 Jan;87(1):3-15. Review.

Wagner JD, Anthony MS, Cline JM. Soy phytoestrogens: research on benefits and risks. Clin Obstet Gynecol. 2001 Dec;44(4):843-52. Review.

Cline JM, Soderqvist G, Register TC, Williams JK, Adams MR, Von Schoultz B. Assessment of hormonally active agents in the reproductive tract of female nonhuman primates. Toxicol Pathol. 2001 Jan-Feb;29(1):84-90. Review.

Wagner JD, Cline JM, Shadoan MK, Bullock BC, Rankin SE, Cefalu WT. Naturally occurring and experimental diabetes in cynomolgus monkeys: a comparison of carbohydrate and lipid metabolism and islet pathology. Toxicol Pathol. 2001 Jan-Feb;29(1):142-8.