© The Author 2007. Published by Oxford University Press.
CORRESPONDENCE |
Re: Age-Related Lobular Involution and Risk of Breast Cancer
Affiliation of authors: Division of Medical Oncology A, Regina Elena Cancer Institute, Rome, Italy
Correspondence to: Gianluigi Ferretti, MD, PhD, Division of Medical Oncology A, Regina Elena Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy (e-mail: gia.fer{at}flashnet.it).
According to Milanese et al. (1), there is an inverse association between lobular involution and parity. Although the persistence of lobular structures caused by subsequent pregnancies could be associated with increased risk of breast cancer, multiparity is generally associated with a reduced risk of breast cancer. The authors hypothesized that "the breast cancer risk modification associated with parity is independent of involution status" (1).
In postlactational involution, the mammary gland regresses to its prepregnant state—fibroblasts secrete proteases that degrade the extracellular matrix proteins, with the consequent release of bioactive matrix fragments that can promote tumor growth, motility, and invasion (2). In contrast, the molecular mechanism of age-related involution has not been characterized by detailed microarray-based surveys. In the study by Milanese et al., the degree of involution for each specimen was categorized by histologic findings according to the extent of lobular involution in the background breast.
A possible biologic mechanism through which failure to undergo involution could influence a patient's breast cancer risk is that stem cells or early progenitors (i.e., the prime targets of intrinsic and/or extrinsic mutagenic stresses) may become quiescent (3). The lobules found in the breast of postmenopausal women, who had an early full-term pregnancy, appear to be composed of epithelial cells that are refractory to transformation (i.e., stem cells or early progenitors) (4). This refractoriness has been associated with the absence of a proliferative response in the parous epithelium when confronted with the carcinogen, compared with the nulliparous gland (5). Parity-induced epithelial cells are pluripotent, committed to secretory cell fate, contribute to the development of secretory lobules after successive pregnancies, and can self-renew over multiple transplant generations (6).
A reduction in the reproductive life span of these multipotent mammary epithelial stem cells in situ results in a statistically significant association with reduced susceptibility to mouse mammary tumor virus–induced mammary tumorigenesis (5). Expression of activated transforming growth factor 
1 by the parity-induced epithelial cells during pregnancy or tissue remodeling in the absence of lactation severely curtails the self-renewing activity of these cells in transplants but not their capacity to proliferate and produce epithelial progeny with diverse fates in the mammary epithelium of multiparous female mice when left in situ (6).
We think that the involution status could be, in part, dependent of parity because, after successive pregnancies, stem and/or progenitor cells accumulate in the mammary glands of multigestational female mice (6). The risk of carcinogenesis in mammary glands might be associated with transformation of these cells by deregulation of self-renewal pathways. In transplants from triple transgenic multiparous female mice, whey acidic protein promoter–transforming growth factor 1–positive parity-induced epithelial cells cannot proliferate expansively or self-renew. Finally, because full-term pregnancies after age 35 years are associated with an increased risk of breast cancer (7), we agree with Milanese et al. that further data on a woman's age at each pregnancy would be helpful in more precisely evaluating the relationships of parity, involution, and breast cancer risk.
REFERENCES
(1) Milanese TR, Hartmann LC, Sellers TA, Frost MH, Vierkant RA, Maloney SD. Age-related lobular involution and risk of breast cancer. J Natl Cancer Inst (2006) 98:1600–7.
(2) Schedin P. Pregnancy-associated breast cancer and metastasis. Nat Rev Cancer (2006) 6:281–91.[CrossRef][ISI][Medline]
(3) Liu S, Dontu GA, Wicha MS. Mammary stem cells, self-renewal pathways, and carcinogenesis. Breast Cancer Res (2005) 7:86–95.[CrossRef][ISI][Medline]
(4) Russo J, Balogh GA, Chen J, Fernandez SV, Fernbaugh R, Heulings R. The concept of stem cell in the mammary gland and its implication in morphogenesis, cancer and prevention. Front Biosci (2006) 11:151–72.[ISI][Medline]
(5) Boulanger CA, Smith GH. Reducing mammary cancer risk through premature stem cell senescence. Oncogene (2001) 20:2264–72.[CrossRef][ISI][Medline]
(6) Boulanger CA, Wagner KU, Smith GH. Parity-induced mouse mammary epithelial cells are pluripotent, self-renewing and sensitive to TGF-beta1 expression. Oncogene (2005) 24:552–60.[CrossRef][ISI][Medline]
(7) Trichopoulos D, Hsieh CC, MacMahon B, Lin TM, Lowe CR, Mirra AP. Age at any birth and breast cancer risk. Int J Cancer (1983) 31:701–4.[ISI][Medline]
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J Natl Cancer Inst 2006 98: 1600-1607.
J Natl Cancer Inst 2007 99: 572.
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