Open Access

Pregnancy offers new insights into mechanisms of breast cancer risk and resistance

  • D Joseph Jerry1, 2Email author,
  • Grace Makari-Judson3,
  • Giovanna M Crisi4 and
  • Karen A Dunphy1, 2
Breast Cancer Research201315:312

https://doi.org/10.1186/bcr3482

Published: 24 September 2013

Abstract

Pregnancy induces long-lasting changes in gene expression that are associated with a reduction in breast cancer risk. Although several mechanisms have been proposed to mediate the reduction in breast cancer risk among parous women, recent studies focus attention on progenitor cells as major targets. The results suggest new biomarkers that may improve risk prediction and provide endpoints for assessment of clinical responses to prophylactic therapies.

Viewpoint

An increased prevalence of breast cancer among Roman Catholic nuns in Italy was observed in the 1600 s, providing early links between reproductive factors and breast cancer risk. Epidemiological studies in the 1970s identified pregnancy as a key factor in reducing the risk of breast cancer. This was evident in a variety of species and reproduced in rodent experiments. This is not a simple relationship, because the incidence of breast cancer is increased transiently during the period immediately after pregnancy in women [1], but the overall effect is that lifetime risk is reduced by up to 50% [2]. Furthermore, the protective mechanisms are robust, rendering the breast epithelium resistant to the carcinogenic effects of ionizing radiation [3] and alkylating agents [4].

Studies in rodents suggest four mechanisms to explain the protection afforded by pregnancy: (a) systemic changes in endocrine factors [5], (b) differentiation of the mammary epithelium- and stroma-reducing proliferative responses [5], (c) sensitization of pro-apoptotic pathways, especially those mediated by p53 [6, 7], and (d) restriction of the progenitor cell population [8]. Transcriptional profiling of mammary tissues revealed stable changes in parous rodents [9]. However, genome-wide transcriptional profiling experiments using human breast tissues containing both epithelial and stromal components yielded variable results. Host factors such as age, obesity, and genetic diversity greatly influence gene expression patterns [10, 11] and may obscure changes in the pathway subset that are responsible for the protective effects of parity. Alternatively, the mechanisms in women may differ from those in mice.

A new study by Choudhury and colleagues [12] addressed this complexity by examining gene expression profiles in subsets of breast epithelium representing luminal (CD24+), myoepithelial (CD24low/CD10+), and progenitor (CD24low/CD10low/CD44+) cells and stromal fibroblasts. Among these cell populations, parity had the greatest effect on gene expression patterns in the CD44+ progenitors. The persistent effects of parity were paralleled by changes in DNA methylation, suggesting an epigenetic mechanism. The effect of parity was surprisingly robust given the limited number and diversity of patients (three nulliparous and three parous, the latter including both an African-American and a Caucasian). These results mirror experiments in mice in the lab of Meier-Abt and colleagues [13], who found that gene expression patterns altered most dramatically in the mammary stem cell population. This was corroborated by functional testing of the progenitor activity in vitro and by transplantation in vivo. Therefore, restriction of the progenitor cell population is a common effect of pregnancy in both mice and women.

The association between breast cancer risk and stem cells has been more difficult to demonstrate. Choudhury and colleagues [12] compared expression profiles of CD44+ progenitor cells from high-risk individuals who were carriers of mutations in breast cancer susceptibility genes BRCA1 and BRCA2 and found patterns to be most similar to nulliparous women regardless of parity. This suggests that parity is less protective in these individuals. However, epidemiological studies have been divided on this point, and the majority of recent studies demonstrated a reduction in risk among parous BRCA1/2 carriers which was similar to that of the general population [14]. The apparent discrepancy may be due to disruptions in cell lineages in the high-risk patients. Using cell sorting, Lim and colleagues [15] found that the breast stem cell population was reduced among the 10 BRCA1 patients analyzed compared with the 30 normal controls. However, the progenitor population committed to the luminal epithelial lineage was increased [15]. Subsequent experiments demonstrated that the hormone receptor-negative luminal progenitors are the ‘cells of origin’ for breast cancers in BRCA1 patients [15, 16]. Therefore, alterations in cell lineages in BRCA1/2 mutation carriers may contribute to the clustering observed by Choudhury and colleagues. As parity has been suggested to engage multiple pathways, it is likely that there are compensatory pathways that confer protection even when the equilibrium of the cell lineages is disrupted.

The broader goal is to develop biomarkers that identify individuals who are at elevated risk and that guide selection of prophylactic therapies. The decrease in cells expressing nuclear p27 (encoded by CDKN2a) among parous women, especially the decrease in hormone-responsive cells that are positive for both p27 and estrogen receptor-alpha (p27+/ER+), is intriguing [12]. The results suggest that quiescent ‘hormone-sensing’ cells are biomarkers of progenitor cell dynamics. The role of the ER+ cells in sensing hormone exposures and regulating progenitor cells was also observed in mice [13]. In these studies, pregnancy reduced secretion of Wnt4, which limited the population of progenitor cells. Both decreases in Wnt signaling and increases in apoptosis were among the pathways altered significantly among CD44+ cells from parous women [12].

These data reveal biomarkers of progenitor cell dynamics that can be applied to assess breast cancer risk and provide surrogate endpoints in trials assessing efficacy of chemopreventive therapies designed to restrain progenitor populations. Selective stimulation of the hormone-sensing cells to restrict Wnt expression or enhance expression of Wnt antagonists, such as secreted frizzled-related proteins, offers novel targets for chemoprevention.

Abbreviation

ER: 

Estrogen receptor.

Declarations

Authors’ Affiliations

(1)
Department of Veterinary & Animal Sciences, Integrated Sciences Building, University of Massachusetts Amherst
(2)
Pioneer Valley Life Sciences Institute
(3)
Department of Hematology and Oncology, Baystate Medical Center
(4)
Department of Pathology, Baystate Medical Center

References

  1. Schedin P: Pregnancy-associated breast cancer and metastasis. Nat Rev Cancer. 2006, 6: 281-291. 10.1038/nrc1839.View ArticlePubMedGoogle Scholar
  2. Albrektsen G, Heuch I, Hansen S, Kvale G: Breast cancer risk by age at birth, time since birth and time intervals between births: exploring interaction effects. Br J Cancer. 2005, 92: 167-175. 10.1038/sj.bjc.6602302.View ArticlePubMedGoogle Scholar
  3. Ronckers CM, Erdmann CA, Land CE: Radiation and breast cancer: a review of current evidence. Breast Cancer Res. 2005, 7: 21-32. 10.1186/bcr970.View ArticlePubMedGoogle Scholar
  4. Russo IH, Russo J: Developmental stage of the rat mammary gland as determinant of its susceptibility to 7,12-dimethylbenz[a]anthracene. J Natl Cancer Inst. 1978, 61: 1439-1449.PubMedGoogle Scholar
  5. Russo IH, Russo J: Physiological bases of breast cancer prevention. Eur J Cancer Prevention. 1993, 2: 101-111. 10.1111/j.1365-2354.1993.tb00176.x.View ArticleGoogle Scholar
  6. Jerry DJ, Kittrell FS, Kuperwasser C, Laucirica R, Dickinson ES, Bonilla PJ, Butel JS, Medina D: A mammary-specific model demonstrates the role of the p53 tumor suppressor gene in tumor development. Oncogene. 2000, 19: 1052-1058. 10.1038/sj.onc.1203270.View ArticlePubMedGoogle Scholar
  7. Medina D, Kittrell FS: p53 function is required for hormone-mediated protection of mouse mammary tumorigenesis. Cancer Res. 2003, 63: 6140-6143.PubMedGoogle Scholar
  8. Siwko SK, Dong J, Lewis MT, Liu H, Hilsenbeck SG, Li Y: Evidence that an early pregnancy causes a persistent decrease in the number of functional mammary epithelial stem cells - implications for pregnancy-induced protection against breast cancer. Stem Cells. 2008, 26: 3205-3209. 10.1634/stemcells.2008-0103.View ArticlePubMedPubMed CentralGoogle Scholar
  9. Blakely CM, Stoddard AJ, Belka GK, Dugan KD, Notarfrancesco KL, Moody SE, D’Cruz CM, Chodosh LA: Hormone-induced protection against mammary tumorigenesis is conserved in multiple rat strains and identifies a core gene expression signature induced by pregnancy. Cancer Res. 2006, 66: 6421-6431. 10.1158/0008-5472.CAN-05-4235.View ArticlePubMedGoogle Scholar
  10. Pirone JR, D’arcy M, Stewart DA, Hines WC, Johnson M, Gould MN, Paul Y, Jerry DJ, Schneider SS, Troester MA: Age-associated gene expression in normal breast tissue mirrors qualitative age-at-incidence patterns for breast cancer. Cancer Epidemiol Biomarkers Prev. 2012, 21: 1735-1744. 10.1158/1055-9965.EPI-12-0451.View ArticlePubMedPubMed CentralGoogle Scholar
  11. Sun X, Casbas-Hernandez P, Bigelow C, Makowski L, Jerry DJ, Schneider SS, Troester MA: Normal breast tissue of obese women is enriched for macrophage markers and macrophage-associated gene expression. Breast Cancer Res Treat. 2012, 131: 1003-1012. 10.1007/s10549-011-1789-3.View ArticlePubMedGoogle Scholar
  12. Choudhury S, Almendro V, Merino VF, Wu Z, Maruyama R, Su Y, Martins FC, Fackler MJ, Bessarabova M, Kowalczyk A, Conway T, Beresford-Smith B, Macintyre G, Cheng YK, Lopez-Bujanda Z, Kaspi A, Hu R, Robens J, Nikolskaya T, Haakensen VD, Schnitt SJ, Argani P, Ethington G, Panos L, Grant M, Clark J, Herlihy W, Lin SJ, Chew G, Thompson EW, et al: Molecular profiling of human mammary gland links breast cancer risk to a p27(+) cell population with progenitor characteristics. Cell Stem Cell. 2013, 13: 117-130. 10.1016/j.stem.2013.05.004.View ArticlePubMedPubMed CentralGoogle Scholar
  13. Meier-Abt F, Milani E, Roloff T, Brinkhaus H, Duss S, Meyer DS, Klebba I, Balwierz PJ, van Nimwegen E, Bentires-Alj M: Parity induces differentiation and reduces Wnt/Notch signaling ratio and proliferation potential of basal stem/progenitor cells isolated from mouse mammary epithelium. Breast Cancer Res. 2013, 15: R36-10.1186/bcr3419.View ArticlePubMedPubMed CentralGoogle Scholar
  14. Milne RL, Osorio A, Ramón y Cajal T, Baiget M, Lasa A, Diaz-Rubio E, de la Hoya M, Caldés T, Teulé A, Lázaro C, Blanco I, Balmaña J, Sánchez-Ollé G, Vega A, Blanco A, Chirivella I, Esteban Cardeñosa E, Durán M, Velasco E, Martínez de Dueñas E, Tejada MI, Miramar MD, Calvo MT, Guillén-Ponce C, Salazar R, San Román C, Urioste M, Benítez J: Parity and the risk of breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat. 2010, 119: 221-232. 10.1007/s10549-009-0394-1.View ArticlePubMedGoogle Scholar
  15. Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH, Asselin-Labat ML, Gyorki DE, Ward T, Partanen A, Feleppa F, Huschtscha LI, Thorne HJ, Fox SB, Yan M, French JD, Brown MA, Smyth GK, Visvader JE, Lindeman GJ, kConFab: Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med. 2009, 15: 907-913. 10.1038/nm.2000.View ArticlePubMedGoogle Scholar
  16. Molyneux G, Geyer FC, Magnay FA, McCarthy A, Kendrick H, Natrajan R, Mackay A, Grigoriadis A, Tutt A, Ashworth A, Reis-Filho JS, Smalley MJ: BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell. 2010, 7: 403-417. 10.1016/j.stem.2010.07.010.View ArticlePubMedGoogle Scholar

Copyright

© BioMed Central Ltd. 2013

Advertisement