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Endocrine and reproductive influences significantly affect the lifetime risk of breast cancer. Nulliparity is one of the most firmly established risk factors for breast cancer, whereas early full-term pregnancy and parity confer a significant protection. The breast attains its maximum development during pregnancy and lactation. After menopause the breast regresses in both nulliparous and parous women containing lobular structures designated lobules type 1 (Lob 1). We have postulated that the degree of differentiation acquired through early pregnancy changes the 'genomic signature' that differentiates the Lob 1 from the early parous women from that of the nulliparous women by shifting the Stem cell 1 to a Stem cell 2, making this the mechanism of protection conferred by early full-term pregnancy. In order to elucidate the molecular pathways through which pregnancy exerts a protective effect, we have analyzed the genomic profile of Lob 1 present in reduction mammoplasty specimens obtained from parous and nulliparous postmenopausal women. The genes differentially expressed are related to immune-surveillance, DNA repair, programmed cell death, transcription, and chromatin structure/ activators/co-activator. In the present study we performed real-time RT-PCR using a low-density array or a microfluid card for genes related to the immune system and programmed cell death, using 18S as an internal control [TaqMan ® Low Density Array Human Immune Panel (Applied Biosystems)]. Breast epithelial cells from parous women significantly overexpressed 17 out of 20 genes (p<0.001) with respect to the nulliparous breast. BCL2-associated X protein, Complement component 3, CD45 antigen, glyceraldehyde-3-phosphate dehydrogenase, granulysin, and chemokine (C-C motif) ligand 19 were expressed more than 30-fold with respect to nulliparous breast cells. Only three out of 20 genes [selectin P (granule membrane protein 140 kDa, antigen CD62), Fas (TNF receptor superfamily, member 6) and chemokine (C-X-C motif) ligand 11], were downregulated in parous breast with respect to nulliparous breast cells. The data lead us to conclude that an early pregnancy, by shifting the Stem cell 1 to Stem cell 2, makes the latter more easily recognized by the immunesurveillance system, which initiates the programmed cell death pathway if exposure to toxic or carcinogenic agents occurs.

Abstract. Breast cancer is the most frequent malignancy in women. It is well recognized that tumorigenesis is a multistep process resulting from the accumulation of sequential genetic alterations. In breast cancers LOH has been described on one or both arms of multiple chromosomes. Comparative genomic hybridization (CGH) analysis was performed to identify chromosomal imbalances in the breast epithelial cells (HBEC). We have used a human in vitro-in vivo system in which the environmental carcinogen benz(a)pyrene (BP) and the c-Ha-ras oncogene were utilized for inducing in vitro transformation of HBEC. Immortal MCF-10F cells were treated with BP which resulted in the transformed cell line BP-1 that was further enhanced by transfection with the cHa-ras to generate the cell line BP-1-Tras. This cell line is tumorigenic when injected in severe combined immunodeficient (SCID) mice, generating the tumor cell line BP-1-Tras T J#4. Our comparative genomic hybridization analysis indicates that the most overrepresented segment after cell transformation and in the BP-1, BP-1-Tras and in the tumor cell line were 1p (80%), 5q21-ter (80%), 8q24.1 (90%) and Xq27-28 (60%). DNA sequence amplification at 10p14-15 was observed in BP-1-Tras T J#4 cells. Allelic losses of chromosome 4, 8p11-21 and 15q11-12, occur after cell transformation and are maintained consistently during tumorigenesis.

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