The Genomic Signature of Breast Cancer Prevention

Abstract

Abstract:The breast of parous postmenopausal women exhibits a specific signature that has been induced by a full term pregnancy. This signature is centered in chromatin remodeling and the epigenetic changes induced by methylation of specific genes which are important regulatory pathways induced by pregnancy. Through the analysis of the genes found to be differentially methylated between women of varying parity, multiple positions at which beta-catenin production and use is inhibited were recognized. The biological importance of the pathways identified in this specific population cannot be sufficiently emphasized because they could represent a safeguard mechanism mediating the protection of the breast conferred by full term pregnancy.

Higher parity and shorter breastfeeding duration

“…8,17 This could theoretically be from repeated failure of an expanded progenitor cell population in breast tissue to naturally undergo differentiation and apoptosis from prolonged breastfeeding, producing a persistent pool of cells with survival capability and at potential risk for carcinogenesis and subsequent development of undifferentiated tumor phenotype (such as triple-negative BC). 8,[10][11][12][13][14][15] However, this hypothetical stochastic model might not predict the interval until cancer is detected, because of variable effects from each pregnancy and lactation, the timing and potency of subsequent carcinogenic events, and differing growth rates according to phenotype. We stress that we did not study progenitor cells or normal postpartum breast tissues from this patient cohort, and we did not directly study parity and breastfeeding as risk factors for future development of triple-negative BC.…”

“…[7][8][9] However, both parity and breastfeeding duration might contribute in combination to risk by altering the population of progenitor cells that are retained within breast parenchyma, a cell type that known to have enhanced survival potential under physiological or pathologic stress. 8,[10][11][12][13][14][15] Indeed, recruitment and expansion of progenitor cells within breast terminal ducts sustains epithelial expansion during pregnancy and lactation, and this is followed by epithelial differentiation or apoptosis during the course of weaning. 16 However, it is not known what minimum duration of breastfeeding might induce differentiation of breast progenitor cells, or whether a combination of higher parity with repeated short or absent breastfeeding might augment the pathogenesis of BC with undifferentiated phenotype.…”

Efeitos morfológicos, histológicos e moleculares dos moduladores seletivos dos receptores de estrogênios tamoxifeno e raloxifeno na prevenção primária de tumores mamários quimicamente induzidos em ratas

“…Muitos animais são utilizados em investigações experimentais para o estudo da carcinogênese mamária, mas, ainda hoje, os roedores são os animais preferidos pelo fácil manuseio, boa relação custo-benefício e pelas semelhanças estruturais e histológicas bem estabelecidas com a espécie humana (Russo et al 1982(Russo et al , 1990(Russo et al , 2005a(Russo et al , 2007Steele et al, 1994;Cardiff et al, 2002;Mehta, 2000;Cheung et al, 2003aCheung et al, , 2003bBlakely et al, 2006).…”

“…O processo de influência hormonal, de diferenciação lobular e de proliferação da célula epitelial mamária é mais acentuado no epitélio de ductos e lóbulos e, menos freqüente, na célula mioepitelial, no estroma interlobular e no intralobular (Russo e Russo, 2004b;Russo et al, 2005aRusso et al, , 2007.…”

“…Nesse sentido, além da melhora gradativa na tecnologia de exames que possam detectar lesões mais precoces (Kopans, 1995;Feig et al, 1998;Olsen e Gotzsche, 2001;Tabar et al, 2001;Feig, 2002;Lee, 2002;Jackson, 2002; Gøtzsche e Nielsen, 2006) e estímulos para mudanças mais saudáveis nos hábitos e estilos de vida, surge a descoberta de novos medicamentos, com o propósito de se fazer a prevenção primária, entre eles substâncias que tenham ação quimioprotetoras na formação do câncer de mama (Fentiman, 2000;Geller e Vogel, 2005;Bao et al, 2006;Grilli, 2006;Jordan, 2006;Kelloff et al, 2006;Jordan, 2007;Russo et al, 2007).…”