Genomic Changes Induced by Pregnancy in Breast Epithelial Cells

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The collections of normal breast tissue that adhere to well-established parameters of normality are extremely difficult to obtain (J. Russo et al. 1988), mainly because the normal human breast tissue must be obtained from women with different reproductive histories. One group must represent the low-risk group composed of post-menopausal women without breast cancer who completed their first full-term pregnancy (FFTP) before age 24. The second group for comparison is postmenopausal women without breast cancer who are nulliparous. The selection of post-menopausal women must be those who are at least 1 year after their last menses if menopause occurred naturally or basal serum follicle stimulating hormone (FSH) greater than 40 ng/ml if menopause was surgical and the participant is less than 60 years old. The age at menarche, day of last menstruation, number of miscarriages, year of first full-term pregnancy, number of pregnancies, and no replacement therapy or previous surgical procedures for benign or malignant diseases of the breast are important conditions for the selection of the samples to be analyzed and as a consequence limit the number of samples available for a large study.

The breast epithelial cells and the stroma of the lobules type 1 found in the breast tissue of postmenopausal parous women has a genomic signature different from similar structures derived from postmenopausal nulliparous women (J. Russo and I.H. Russo 1997). Those genes that are significantly different are grouped in major categories based on their putative functional significance. Among them are those gene transcripts related to a) immune-surveillance, b) DNA repair and programmed cell death, and c) transcription, chromatin structure/activators/co activator (Balogh et al. 2006) (Table 1).

Role of Immune Surveillance-Related Genes in the Parous Breast

In breast epithelial cells of parous women, four gene transcripts were significantly upregulated (Table 1). The cytoplasmic Toll/interleukin-1 receptor (TIR) (Sanghavi et al. 2004) signaling domain is known to be instrumental in inducing a signaling cascade upon recognition of specific ligand, triggering innate immune responses (Yamamoto and Akira 2004). The T cell receptor VP 1 (TCRP) in breast tumors recognize specific cytotoxic T lymphocytes in a major histocompatibility complex (MHC) unrestricted fashion (Ito et al. 1997; Kirii et al. 1998). The breast epithelial cells of the parous breast also have upregulated the MHC class I HLA-A24. HLA-A24-binding peptides have the capacity to elicit anti-tumor cytotoxic T lymphocytes (CTL) in vitro (Nukaya et al. 1999). It has been shown that HLA class I antigen downregulation is associated with worse clinical course of ovarian carcinoma, which may reflect the escape of tumor cells from immune recognition and destruction (Vitale et al. 2005). The epithelial cells of the parous breast also upregulated the expression of interleukin 22 receptor (Table 1). Interleukin-22 (IL-22) is a member of interferon/IL-10 family, which plays an important role in immune response through activation of the STAT 3 signal transduction pathway (Wei et al. 2003; Donnelly et al. 2004; Wolk et al. 2004). The enhanced immune-surveillance mechanism that has been imprinted because of the differentiation cycle induced by pregnancy could be one of the protective factors induced by the cells against neoplastic initiation or progression. Contrary to the postmenopausal parous breast epithelial cells, those cells derived from the lobules type 1 of the postmenopausal nulliparous women presented an upregulation of the gene transcript for the dendritic cell protein (GA17). The potential role of this dendritic cell protein in the epithelial cells of the nulliparous breast could be explained by the recent publication of Thomachot et al. (2004), who have found that primary breast carcinomas are frequently infiltrated by dendritic cells. The breast carcinoma cells produce soluble factors, which may attract dendritic cells and their precursors in vivo and promote the differentiation of the latter into Langerhans cells and immature dendritic cells with altered functional capacities. The infiltration of breast cancer by these altered dendritic cells may contribute to the impaired immune response against the tumor (Thomachot et al. 2004). This mechanism was partly driven by a TGF^-dependent mechanism since a pan-TGFp polyclonal antibody completely blocks breast cancer cell-induced Langerhans cell differentiation and partly reduces immature dendritic cell development (Thomachot et al. 2004). These data indicate that if this mechanism takes place in the nulliparous breast the dendritic cells normally present in the breast tissue under the action of initiated breast epithelia will be unable to initiate the immune surveillance mechanism of protection. This is supported by the data that TGFp is not overexpressed in the nulliparous mammary gland (D'Cruz et al. 2002).

Table 1 Genes differentially expressed in the postmenopausal breast of parous and nulliparous women

Gene name





Sterile alpha and TIR motif containing 1

1.96 ± 0.09

1.00 ± 0.36

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