Abstract
Background. Tumor cell proliferation is one of the most significant predictors of prognosis for women with breast cancer. Personal characteristics that affect hormonal exposure have been implicated in breast tumor etiology, and it is possible that they may also influence tumor cell proliferation. We examined the association between hormone-related breast cancer risk factors and breast tumor proliferation, as reflected in two proliferation measures, Ki-67 and mitotic count.
Methods. The study population was 484 women 40 years of age and older, who were members of a managed care organization's breast cancer screening program and were diagnosed with invasive breast cancer between 1988 and 1995. The percent of Ki-67 positive tumor cells averaged over four high powered fields (Ki-67) was log transformed and analyzed in a linear regression model. Mitotic count was dichotomized into high versus low (≤10), and analyzed in an unconditional logistic regression model with the odds ratio (OR) as the measure of association.
Results. Consistent with other studies, there was a significant trend of decreased tumor cell proliferation with increasing age (p for trend <0.05 for both measures). Higher body weight was associated with higher Ki-67 (p for trend <0.05), but not with higher mitotic count. We found no significant associations between any reproductive factors (age at menarche, parity, age at first birth, menopausal status and age at menopause) and either measure of tumor cell proliferation. We observed an association between reduced tumor proliferation, as measured by mitotic count and former/current use of hormone replacement therapy (HRT) in comparison to never use (adjusted OR's: former HRT use: 0.40 (95% CI 0.19–0.85); current HRT use: 0.52 (95% CI 0.26–1.04).
Conclusion. Certain factors related to hormonal exposure that influence breast tumor etiology, for example, age, also appear to increase tumor growth. Conversely HRT use, which clearly increases breast cancer risk, may not adversely affect, and possibly may diminish cell proliferation once tumors are established.
Similar content being viewed by others
References
Schneider J, Huh MM, Bradlow HL, Fishman J: Antiestrogen action of 2-hydroxyestrone on MCF-7 human breast cancer cells. J Biol Chem 259: 4840–4845, 1984
Noguchi M, Thomas M, Koyasaki N et al.: Influence of hormones on tumor growth, cell kinetics, estrogen receptor and insulin-like growth factor-I-related protein of human breast cancer (MCF-7) cells transplanted in nude mice. Mol Cell Endocrinol 92: 69–76, 1993
Hug V, Drewinko B, Hortobagyi GN, Blumenschein G: Regulation of breast tumor growth by high dose estrogen is independent of the presence of estrogen receptors. Breast Cancer Res Treat 6: 237–240, 1985
Writing Group for the Women’s Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288: 321–333, 2002
Chen CL, Weiss NS, Newcomb P, Barlow W, White E: Hormone replacement therapy in relation to breast cancer. JAMA 287: 734–741, 2002
Newcomb PA, Titus-Ernstoff L, Egan KM et al.: Postmenopausal estrogen and progestin use in relation to breast cancer risk. Cancer Epidemiol Biomarkers Prev 11: 593–600, 2002
Colditz GA: Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer. J Natl Cancer Inst 90: 814–823, 1998
Cleary MP, Maihle NJ: The role of body mass index in the relative risk of developing premenopausal versus postmenopausal breast cancer. Proc Soc Exp Biol Med 216: 28–43, 1997
Collaborative Group on Hormonal Factors in Breast Cancer: Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 350: 1047–1059, 1997
Kelsey JL, Bernstein L: Epidemiology and prevention of breast cancer. Annu Rev Public Health 17: 47–67, 1996
McGurrin JF, Doria MI Jr., Dawson PJ, Karrison T, Stein HO, Franklin WA: Assessment of tumor cell kinetics by immunohistochemistry in carcinoma of breast. Cancer 59: 1744–1750, 1987
Dressler LG, Seamer LC, Owens MA, Clark GM, McGuire WL: DNA flow cytometry and prognostic factors in 1331 frozen breast cancer specimens. Cancer 61: 420–427, 1988
Gentili C, Sanfilippo O, Silvestrini R: Cell proliferation and its relationship to clinical features and relapse in breast cancers. Cancer 48: 974–979, 1981
Mirecka J, Korabiowska M, Schauer A: Correlation between the occurrence of Ki-67 antigen and clinical parameters in human breast carcinoma. Folia Histochem Cytobiol 31: 83–86, 1993
Meyer JS, Friedman E, McCrate MM, Bauer WC: Prediction of early course of breast carcinoma by thymidine labeling. Cancer 51: 1879–1886, 1983
Brekelmans CT, van Gorp JM, Peeters PH, Collette HJ: Histopathology and growth rate of interval breast carcinoma. Characterization of different subgroups. Cancer 78: 1220–1228, 1996
Diab SG, Elledge RM, Clark GM: Tumor characteristics and clinical outcome of elderly women with breast cancer. J Natl Cancer Inst 92: 550–556, 2000
Muss HB, Kute TE, Case LD et al.: The relation of flow cytometry to clinical and biologic characteristics in women with node negative primary breast cancer. Cancer 64: 1894–1900, 1989
Romero H, Schneider J, Burgos J, Bilbao J, Rodriguez-Escudero FJ: S-phase fraction identifies high-risk subgroups among DNA-diploid breast cancers. Breast Cancer Res Treat 38: 265–275, 1996
Bloom HJG, Richardson WW, Harries EJ: Natural history of untreated breast cancer (1805-1933): comparison of untreated and treated cases according to histologic grade of malignancy. Br Med J 2: 213–221, 1962
Genestie C, Zafrani B, Asselain B et al.: Comparison of the prognostic value of Scarff-Bloom-Richardson and Nottingham histological grades in a series of 825 cases of breast cancer: major importance of the mitotic count as a component of both grading systems. Anticancer Res 18: 571–576, 1998
Clayton F: Pathologic correlates of survival in 378 lymph node-negative infiltrating ductal breast carcinomas. Mitotic count is the best single predictor. Cancer 68: 1309–1317, 1991
Goodson WH III, Moore DH II, Ljung BM et al.: The prognostic value of proliferation indices: a study with in vivo bromodeoxyuridine and Ki-67. Breast Cancer Res Treat 59: 113–123, 2000
Molino A, Micciolo R, Turazza M et al.: Ki-67 immunostaining in 322 primary breast cancers: associations with clinical and pathological variables and prognosis. Int J Cancer 74: 433–437, 1997
Brown RW, Allred CD, Clark GM, Osborne CK, Hilsenbeck SG: Prognostic value of Ki-67 compared to S-phase fraction in axillary node-negative breast cancer. Clin Cancer Res 2: 585–592, 1996
Rudas M, Gnant MF, Mittlbock M et al.: Thymidine labeling index and Ki-67 growth fraction in breast cancer: comparison and correlation with prognosis. Breast Cancer Res Treat 32: 165–175, 1994
Wintzer HO, Zipfel I, Schulte-Monting J, Hellerich U, von Kleist S: Ki-67 immunostaining in human breast tumors and its relationship to prognosis. Cancer 67: 421–428, 1991
Carter AP, Thompson RS, Bourdeau RV, Andenes J, Mustin H, Straley H: A clinically effective breast cancer screening program can be cost-effective, too. Prev Med 16: 19–34, 1987
Taplin SH, Mandelson MT, Anderman C et al.:Mammography diffusion and trends in late-stage breast cancer: evaluating outcomes in a population. Cancer Epidemiol Biomarkers Prev 6: 625–631, 1997
Elston CW, Ellis IO: Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19: 403–410, 1991
Lehr HA, Hansen DA, Kussick S et al.: Assessment of proliferative activity in breast cancer: MIB-1 immunohistochemistry versus mitotic figure count. Hum Pathol 30: 1314–1320, 1999
Weidner N, Moore DH II, Ljung BM et al.: Correlation of bromodeoxyuridine (BRDU) labeling of breast carcinoma cells 142 N Oestreicher et al. with mitotic figure content and tumor grade. Am J Surg Pathol 17: 987–994, 1993
Andersen J, Poulsen HS: Immunohistochemical estrogen receptor determination in paraffin-embedded tissue. Prediction of response to hormonal treatment in advanced breast cancer. Cancer 64: 1901–1908, 1989
Ravn V, Havsteen H, Thorpe SM: Immunohistochemical evaluation of estrogen and progesterone receptors in paraffinembedded, formalin-fixed endometrial tissues: comparison with enzyme immunoassay and immunohistochemical analysis of frozen tissue. Mod Pathol 11: 709–715, 1998
Zafrani B, Aubriot MH, Mouret E et al.: High sensitivity and specificity of immunohistochemistry for the detection of hormone receptors in breast carcinoma: comparison with biochemical determination in a prospective study of 793 cases. Histopathology 37: 536–545, 2000
Cattoretti G, Becker MH, Key G et al.: Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol 168: 357–363, 1992
Porter PL, Malone KE, Heagerty PJ et al.: Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nat Med 3: 222–225, 1997
Potischman N, Swanson CA, Siiteri P, Hoover RN: Reversal of relation between body mass and endogenous estrogen concentrations with menopausal status. J Natl Cancer Inst 88: 756–758, 1996
Walker RA, Lees E, Webb MB, Dearing SJ: Breast carcinomas occurring in young women (<35 years) are different. Br J Cancer 74: 1796–1800, 1996
Reid SE, Murthy MS, Kaufman M, Scanlon EF: Endocrine and paracrine hormones in the promotion, progression and recurrence of breast cancer. Br J Surg 83: 1037–1046, 1996
Olsson H, Jernstrom H, Alm P et al.: Proliferation of the breast epithelium in relation to menstrual cycle phase, hormonal use, and reproductive factors. Breast Cancer Res Treat 40: 187–196, 1996
de Waard F, Trichopoulos D: A unifying concept of the aetiology of breast cancer. Int J Cancer 41: 666–669, 1988
Zhang S, Folsom AR, Sellers TA, Kushi LH, Potter JD: Better breast cancer survival for postmenopausal women who are less overweight and eat less fat. The Iowa Women’s Health Study. Cancer 76: 275–283, 1995
Newman SC, Lees AW, Jenkins HJ: The effect of body mass index and oestrogen receptor level on survival of breast cancer patients. Int J Epidemiol 26: 484–490, 1997
Yager JD: Endogenous estrogens as carcinogens through metabolic activation. J Natl Cancer Inst Monogr 27: 67–73, 2000
Cobleigh MA, Norlock FE, Oleske DM, Starr A: Hormone replacement therapy and high S phase in breast cancer. JAMA 281: 1528–1530, 1999
Holli K, Isola J, Cuzick J: Low biologic aggressiveness in breast cancer in women using hormone replacement therapy. J Clin Oncol 16: 3115–3120, 1998
Friedman DR, Dubin N: Case-control evaluation of breast cancer screening efficacy. Am J Epidemiol 133: 974–984, 1991
LeBlanc ES, Viscoli CM, Henrich JB: Postmenopausal estrogen replacement therapy is associated with adverse breast cancer prognostic indices. J Womens Health Gend Based Med 8: 815–823, 1999
Cheek J, Lacy J, Toth-Fejel S, Morris K, Calhoun K, Pommier RF: The impact of hormone replacement therapy on the detection and stage of breast cancer. Arch Surg 137: 1015–1019, 2002
Schairer C, Gail M, Byrne C et al.: Estrogen replacement therapy and breast cancer survival in a large screening study. J Natl Cancer Inst 91: 264–270, 1999
Grodstein F, Stampfer MJ, Colditz GA et al.: Postmenopausal hormone therapy and mortality. N Engl J Med 336: 1769–1775, 1997
Bonnier P, Romain S, Giacalone PL, Laffargue F, Martin PM, Piana L: Clinical and biologic prognostic factors in breast cancer diagnosed during postmenopausal hormone replacement therapy. Obstet Gynecol 85: 11–17, 1995
Jernstrom H, Frenander J, Ferno M, Olsson H: Hormone replacement therapy before breast cancer diagnosis significantly reduces the overall death rate compared with never-use among 984 breast cancer patients. Br J Cancer 80: 1453–1458, 1999
Nanda K, Bastian LA, Schulz K: Hormone replacement therapy and the risk of death from breast cancer: a systematic review. Am J Obstet Gynecol 186: 325–334, 2002
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Oestreicher, N., White, E., Malone, K.E. et al. Hormonal Factors and Breast Tumor Proliferation: Do Factors that Affect Cancer Risk also Affect Tumor Growth?. Breast Cancer Res Treat 85, 133–142 (2004). https://doi.org/10.1023/B:BREA.0000025402.70958.3e
Issue Date:
DOI: https://doi.org/10.1023/B:BREA.0000025402.70958.3e