© The Author 2006. Published by Oxford University Press.
EDITORIAL |
Breast Cancer Heterogeneity: A Mixture of At Least Two Main Types?
Affiliation of authors: Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
Correspondence to: William F. Anderson, MD, MPH, Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Room 8036, 6120 Executive Blvd., Bethesda, MD 20892-7244 (e-mail: wanderso{at}mail.nih.gov).
Breast cancers are clinically heterogeneous (1). However, breast cancer etiologic heterogeneity is not so well established. Traditionally, breast cancer has been viewed as one biologic entity with common etiology (2). Much like the adenoma-to-carcinoma sequence for colorectal cancer (3–6), breast cancers supposedly result from stochastic molecular changes over long periods. Stepwise molecular alterations are mirrored by histologic progression from normal breast epithelium to atypical hyperplasias to carcinoma in situ to invasive breast cancer (7,8).
Accumulating facts challenge this purely stochastic view (9). Emerging data demonstrate that the stratification of tumors by gene expression profiles (10–14) and other techniques (15–17) divides breast cancer into a mixture of at least two main types, with five subtypes, according to hormone receptor expression (negative or positive) and/or epithelial cellular origin (basal or luminal). The hormone receptor–negative (basal) group has three subtypes—one with HER2 overexpression, one "normal-like," and one basal subtype with positive epidermal growth factor receptor (EGFR), absent estrogen receptor (ER), absent progesterone receptor (PR), and absent HER2 expression (i.e., the so-called triple-negative subtype). The hormone receptor–positive group has two subtypes—luminal A and luminal B. Human ER-negative and basal tumors are parenthetically associated with the rare medullary carcinomas and mutations in the BRCA1 gene (18–22).
In this issue of the Journal, Asselin-Labat et al. examined expression profiles in normal mouse mammary stem cells (23). Using purification methods for the prospective and differential isolation of adult mouse mammary epithelial cells (24,25), they identified a hierarchical parent–progeny relationship between mouse mammary stem cells and their derivative colony-forming cell progeny. Mouse mammary stem cells expressed CD24+ along with relatively high levels of CD29 or CD49 and coexpressed myoepithelial cellular markers that were similar to those expressed by human basal breast cancers. Their derivative colony-forming cell progeny expressed CD24+ along with relatively low levels of CD29 or CD49 and coexpressed markers with luminal features.
The authors then evaluated hormone receptor expression and other prognostic markers in the mouse mammary stem cell (or basal-like) and their derivative colony-forming progeny (or luminal) populations. Mouse mammary stem cell-enriched (basal) cells expressed EGFR but did not express ER, PR, or HER2 (consistent with the triple-negative phenotype of human breast tumors). These stem cells also expressed other hallmarks of human basal tumors, such as p63. In contrast, their derivative colony-forming cell progeny (luminal) expressed ER and PR but did not express HER2, EGFR, and p63. Oophorectomy of 8-week-old virgin mice had no effect on the mouse mammary stem cell (basal) population but suppressed their derivative colony-forming cell progeny (luminal).
These findings in mice support a cancer stem cell (or tumor-initiating cell) and/or mixture model for the human breast (or breast cancer) (26–29). In this hierarchical (or stem cell) model, the normal human breast evolves from stem cells of the terminal duct lobular unit (30), a two-cell anatomic complex composed of basal (myoepithelial) and luminal (glandular) epithelial components. After a tumor-initiating or gatekeeper event (31), tumor progression and promotion result in breast cancers with either 1) basal cellular differentiation and negative hormone receptor expression or 2) luminal cellular differentiation and positive hormone receptor expression.
Consistent with a stem cell and/or mixture breast cancer model, epidemiologic data show that the classically recognized inflection point in age-specific breast cancer rates at menopause [Clemmesen's Hook (32)] reflects the confluence of two different rate curves, according to estrogen receptor expression (33). Unlike most epithelial tumors, which have linear age-specific rates on a log–log scale (34,35), rates for ER-negative tumors increase rapidly until age 50 years and then flatten or fall (Fig. 1, A). Rates for ER-positive tumors increase rapidly until age 50 years then continue to rise at a slower pace. Rates for ER-negative tumors show a bimodal breast cancer population, with predominant early-onset mode or peak frequency near age 50 years (Fig. 1, B). ER-positive rates are associated with a mostly late-onset cancer population and mode near age 70 years. Similar bimodal incidence patterns are observed for tumor size (large versus small), lymph node status (positive versus negative), grade (high versus low), and PR status (negative versus positive) with modal ages of 50 and 70 years (36).
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The apparent differences in age incidence patterns suggest, somewhat paradoxically, that premenopausal hormonal exposures have greater impact on ER-negative than on ER-positive tumors (33,37,38). The timing of hormonal exposures as well as the distinction between tumor initiation and promotion or progression may partly explain this dual age-related effect (33,39). For example, premenopausal tamoxifen and oophorectomy appear to reduce hereditary and somatic breast cancers across all levels of risk, whereas postmenopausal tamoxifen prevents ER-positive but not ER-negative disease (40–44). Furthermore, hormone-dependent carcinogenesis might theoretically initiate an ER-negative progenitor with the subsequent capacity for hormone-independent promotion or progression, whereas hormone-independent genetic alterations and/or exposures could initiate an ER-positive cancer that was hormone dependent for tumor promotion or progression. A critical review of 31 publications, indeed, found differential effects for reproductive risk factors by ER expression (45). Analysis of data from a case–control study in Poland has strengthened support for this view (46). Differential associations for reproductive hormonal exposures according to hormone receptor status also have been observed in the Nurses' Health Study (47) and Women's Health Initiative (48).
Moreover, ER-negative and ER-positive breast cancers are differentially linked to screening mammography (49–52), with ER-negative tumors less likely than ER-positive cancers to be screen-detected. ER concentration tends to be inversely associated with HER2 overexpression (53,54). ER-negative and ER-positive tumors respond differently to chemoprevention and to systemic hormonal and/or chemotherapy (43,55–58). An increasing amount of data also demonstrate distinct clinical and molecular portraits for ER expression as tumors progress from early to late stages (59,60). Indeed, the hazard function for breast cancer death reveals two different prognostic patterns for ER-negative and ER-positive breast cancers (Fig. 1, C) (36,61).
In conclusion, the mouse model system of Asselin-Labat et al. appears to support a large body of emerging—as well as established molecular, epidemiologic, and clinical—evidence that is consistent with a stem cell or mixture breast cancer model, resulting in at least two main breast cancer types according to epithelial cellular origin and/or hormone responsiveness. Clinicians, in fact, have long suspected two main breast cancer types (62–67), which are mixed within the general population. The first breast cancer is early onset with peak incidence near age 50 years and hormone dependent (39,68). The second breast cancer is late onset with peak incidence near age 70 years and largely hormone independent.
These data provide opportunity for reflection and change. At a minimum, breast cancer can no longer be viewed as one biologic entity. The concept of a stem cell or mixture model could form the basis for revised conceptual frameworks. For if breast cancer overall consists of a mixture of at least two main types, we need a stratified rather than a unified approach for breast cancer research, prevention, and treatment. For example, breast cancer research must consider subgroup as well as main effects. Breast cancer prevention must focus on tumor-initiating or gatekeeper events. Breast cancer therapy must target the undifferentiated, self-renewing, and cancer-initiating stem cell population.
NOTES
Supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health.
REFERENCES
(1) Henderson IC, Patek AJ. The relationship between prognostic and predictive factors in the management of breast cancer. Breast Cancer Res Treat 1998;52:261–88.[CrossRef][Web of Science][Medline]
(2) Key TJ, Verkasalo PK, Banks E. Epidemiology of breast cancer. Lancet Oncol 2001;2:133–40.[CrossRef][Medline]
(3) Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988;319:525–32.[Abstract]
(4) Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759–67.[CrossRef][Web of Science][Medline]
(5) Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends Genet 1993;9:138–41.[CrossRef][Web of Science][Medline]
(6) Fearon ER. Molecular genetic studies of the adenoma-carcinoma sequence. Adv Intern Med 1994;39:123–47.[Web of Science][Medline]
(7) Hellman S. Natural history of small breast cancers. J Clin Oncol 1994;12:2229–34.
(8) Fuqua SA, Wiltschke C, Zhang QX, Borg A, Castles CG, Friedrichs WE, et al. A hypersensitive estrogen receptor-alpha mutation in premalignant breast lesions. Cancer Res 2000;60:4026–9.
(9) Bernards R, Weinberg RA. Metastasis genes: a progression puzzle. Nature 2002;418:823.[CrossRef][Medline]
(10) Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature 2000;406:747–52.[CrossRef][Medline]
(11) Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 2003;100:8418–23.
(12) Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM, Jazaeri A, et al. Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci U S A 2003;100:10393–8.
(13) West M, Blanchette C, Dressman H, Huang E, Ishida S, Spang R, et al. Predicting the clinical status of human breast cancer by using gene expression profiles. Proc Natl Acad Sci U S A 2001;98:11462–7.
(14) Sorlie T, Wang Y, Xiao C, Johnsen H, Naume B, Samaha RR, et al. Distinct molecular mechanisms underlying clinically relevant subtypes of breast cancer: gene expression analyses across three different platforms. BMC Genomics 2006;7:127.[CrossRef][Medline]
(15) Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 2004;10:5367–74.
(16) Abd El-Rehim DM, Ball G, Pinder SE, Rakha E, Paish C, Robertson JF, et al. High-throughput protein expression analysis using tissue microarray technology of a large well-characterized series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analysis. Int J Cancer 2005;116:340–50.[CrossRef][Web of Science][Medline]
(17) Boecker W, Buerger H. Evidence of progenitor cells of glandular and myoepithelial cell lineages in the human adult female breast epithelium: a new progenitor (adult stem) cell concept. Cell Prolif 2003;36 Suppl 1:73–84.
(18) Lakhani SR, Gusterson BA, Jacquemier J, Sloane JP, Anderson TJ, van de Vijver MJ, et al. The pathology of familial breast cancer: histological features of cancers in families not attributable to mutations in BRCA1 or BRCA2. Clin Cancer Res 2000;6:782–9.
(19) Claus EB, Risch N, Thompson WD, Carter D. Relationship between breast histopathology and family history of breast cancer. Cancer 1993;71:147–53.[CrossRef][Web of Science][Medline]
(20) Claus EB, Risch NJ, Thompson WD. Age at onset as an indicator of familial risk of breast cancer. Am J Epidemiol 1990;131:961–72.
(21) Foulkes WD, Stefansson IM, Chappuis PO, Begin LR, Goffin JR, Wong N, et al. Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 2003;95:1482–5.
(22) Anderson WF, Chu KC, Chang S, Sherman ME. Comparison of age-specific incidence rate patterns for different histopathologic types of breast carcinoma. Cancer Epidemiol Biomarkers Prev 2004;13:1128–35.
(23) Asselin-Labat M-L, Shackleton M, Stingl J, Vaillant F, Forrest NC, Eaves CJ, et al. Steroid hormone receptor status of mouse mammary stem cells. J Natl Cancer Inst 2006;98:1011–4.
(24) Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML, et al. Generation of a functional mammary gland from a single stem cell. Nature 2006;439:84–8.[CrossRef][Medline]
(25) Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D, et al. Purification and unique properties of mammary epithelial stem cells. Nature 2006;439:993–7.[Medline]
(26) Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3:730–7.[CrossRef][Web of Science][Medline]
(27) Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001;414:105–11.[CrossRef][Medline]
(28) Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. From the cover: Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 2003;100:3983–8.
(29) Wang JC, Dick JE. Cancer stem cells: lessons from leukemia. Trends Cell Biol 2005;15:494–501.[CrossRef][Web of Science][Medline]
(30) Wellings SR. A hypothesis of the origin of human breast cancer from the terminal ductal lobular unit. Pathol Res Pract 1980;166:515–35.[Web of Science][Medline]
(31) Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med 2004;10:789–99.[CrossRef][Web of Science][Medline]
(32) Clemmesen J. Carcinoma of the breast. Br J Rad 1948;21:583–90.
(33) Anderson WF, Chatterjee N, Ershler WB, Brawley OW. Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology, and End Results database. Breast Cancer Res Treat 2002;76:27–36.[CrossRef][Web of Science][Medline]
(34) Armitage P, Doll R. A two-stage theory of carcinogenesis in relation to the age distribution of human cancer. Br J Cancer 1957;11:161–9.[Web of Science][Medline]
(35) Armitage P, Doll R. The age distribution of cancer and a multi-stage theory of carcinogenesis. Br J Cancer 1954;8:1–12.[Web of Science][Medline]
(36) Anderson WF, Jatoi I, Devesa SS. Distinct breast cancer incidence and prognostic patterns in the NCI's SEER program: suggesting a possible link between etiology and outcome. Breast Cancer Res Treat 2005;90:127–37.[CrossRef][Web of Science][Medline]
(37) Yasui Y, Potter JD. The shape of age-incidence curves of female breast cancer by hormone-receptor status. Cancer Causes Control 1999;10:431–7.[CrossRef][Web of Science][Medline]
(38) Tarone RE, Chu KC. The greater impact of menopause on ER- than ER+ breast cancer incidence: a possible explanation (United States). Cancer Causes Control 2002;13:7–14.[CrossRef][Web of Science][Medline]
(39) Anderson WF. Puberty and genetic susceptibility to breast cancer (correspondence). N Engl J Med 2003;349:1088–9.
(40) Narod SA, Brunet JS, Ghadirian P, Robson M, Heimdal K, Neuhausen SL, et al. Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Hereditary Breast Cancer Clinical Study Group. Lancet 2000;356:1876–81.[CrossRef][Web of Science][Medline]
(41) Rebbeck TR, Lynch HT, Neuhausen SL, Narod SA, Van't Veer L, Garber JE, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002;346:1616–22.
(42) Kauff ND, Satagopan JM, Robson ME, Scheuer L, Hensley M, Hudis CA, et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002;346:1609–15.
(43) Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast And Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371–88.
(44) Domchek SM, Friebel TM, Neuhausen SL, Wagner T, Evans G, Isaacs C, et al. Mortality after bilateral salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: a prospective cohort study. Lancet Oncol 2006;7:223–9.[CrossRef][Web of Science][Medline]
(45) Althuis MD, Fergenbaum JH, Garcia-Closas M, Brinton LA, Madigan MP, Sherman ME. Etiology of hormone receptor-defined breast cancer: a systematic review of the literature. Cancer Epidemiol Biomarkers Prev 2004;13:1558–68.
(46) Garcia-Closas M, Brinton LA, Lissowska J, Chatterjee N, Peplonska B, Szeszenia-Dabrowska N, et al. Established risk factors for breast cancer by tumor characteristics in Poland. Br J Cancer. In press 2006.
(47) Colditz GA, Rosner BA, Chen WY, Holmes MD, Hankinson SE. Risk factors for breast cancer according to estrogen and progesterone receptor status. J Natl Cancer Inst 2004;96:218–28.
(48) Chlebowski RT, Chen Z, Anderson GL, Rohan T, Aragaki A, Lane D, et al. Ethnicity and breast cancer: factors influencing differences in incidence and outcome. J Natl Cancer Inst 2005;97:439–48.
(49) Narod SA, Dube MP. Re: Biologic characteristics of interval and screen-detected breast cancers. J Natl Cancer Inst 2001;93:151–2.
(50) Porter PL, El-Bastawissi AY, Mandelson MT, Lin MG, Khalid N, Watney EA, et al. Breast tumor characteristics as predictors of mammographic detection: comparison of interval- and screen-detected cancers. J Natl Cancer Inst 1999;91:2020–8.
(51) Gilliland FD, Joste N, Stauber PM, Hunt WC, Rosenberg R, Redlich G, et al. Biologic characteristics of interval and screen-detected breast cancers. J Natl Cancer Inst 2000;92:743–9.
(52) Anderson WF, Jatoi I, Devesa SS. Assessing the impact of screening mammography: breast cancer incidence and mortality rates in Connecticut (1943–2002). Breast Cancer Res Treat 2006 May 9 [Epub ahead of print].
(53) Konecny G, Pauletti G, Pegram M, Untch M, Dandekar S, Aguilar Z, et al. Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst 2003;95:142–53.
(54) Burstein HJ. The distinctive nature of HER2-positive breast cancers. N Engl J Med 2005;353:1652–4.
(55) Jensen EV, Block GE, Smith S, Kyser K, DeSombre ER. Estrogen receptors and breast cancer response to adrenalectomy. J Natl Cancer Inst Monogr 1971;34:55–70.[Medline]
(56) Lippman ME, Allegra JC, Thompson EB, Simon R, Barlock A, Green L, et al. The relation between estrogen receptors and response rate to cytotoxic chemotherapy in metastatic breast cancer. N Engl J Med 1978;298:1223–8.[Abstract]
(57) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687–717.[CrossRef][Web of Science][Medline]
(58) Berry DA, Cirrincione C, Henderson IC, Citron ML, Budman DR, Goldstein LJ, et al. Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 2006;295:1658–67.
(59) Robertson JF. Oestrogen receptor: a stable phenotype in breast cancer. Br J Cancer 1996;73:5–12.[Web of Science][Medline]
(60) Lacroix M, Toillon RA, Leclercq G. Stable ‘portrait’ of breast tumors during progression: data from biology, pathology and genetics. Endocr Relat Cancer 2004;11:497–522.
(61) Anderson WF, Chen BE, Jatoi I, Rosenberg PS. Effects of estrogen receptor expression and histopathology on annual hazard rates of death from breast cancer. Breast Cancer Res Treat 2006 May 10 [Epub ahead of print].
(62) Lilienfeld AM, Johnson EA. The age distribution in female breast and genital cancers. Cancer 1955;8:875–82.[CrossRef][Web of Science][Medline]
(63) De Waard F, De Laive JW, Baanders-van Halewijn EA. On bimodal age distribution of mammary carcinoma. Br J Cancer 1960;14:437–48.[Medline]
(64) Fox MS. On the diagnosis and treatment of breast cancer. JAMA 1979;241:489–94.
(65) Manton KG, Stallard E. A two-disease model of female breast cancer: mortality in 1969 among white females in the United States. J Natl Cancer Inst 1980;64:9–16.[Web of Science][Medline]
(66) Adami HO. Breast cancer incidence and mortality. Aspects on aetiology, time trends and curability. Acta Chir Scand 1984;519(Suppl):9–14.
(67) Fitzpatrick PJ. A tale of two women: the concept of good and bad disease in breast cancer. Can J Surg 1986;29:78–9.[Web of Science][Medline]
(68) Moolgavkar SH, Lee JA, Hade RD. Comparison of age-specific mortality from breast cancer in males in the United States and Japan. J Natl Cancer Inst 1978;60:1223–5.[Web of Science][Medline]
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