Molecular basis of pregnancy-induced breast cancer protection

Abstract

We have postulated that the lifetime protective effect of an early pregnancy against breast cancer is due to the complete differentiation of the mammary gland characterized by a specific genomic signature imprinted by the physiological process of pregnancy. In the present work, we show evidence that the breast tissue of postmenopausal parous women has had a shifting of stem cell 1 to stem cell 2 with a genomic signature different from similar structures derived from postmenopausal nulliparous women that have stem cell 1. Those genes that are significantly different are grouped in major categories on the basis of their putative functional significance. Among them are those gene transcripts related to immune surveillance, DNA repair, transcription, chromatin structure/activators/co-activators, growth factor and signal transduction pathway, transport and cell trafficking, cell proliferation, differentiation, cell adhesion, protein synthesis and cell metabolism. From these data, it was concluded that during pregnancy there are significant genomic changes that reflect profound alterations in the basic physiology of the mammary gland that explain the protective effect against carcinogenesis. The implication of this knowledge is that when the genomic signature of protection or refractoriness to carcinogenesis is acquired by the shifting of stem cell 1 to stem cell 2, the hormonal milieu induced by pregnancy or pregnancy-like conditions is no longer required. This is a novel concept that challenges the current knowledge that a chemopreventive agent needs to be given for a long period to suppress a metabolic pathway or abrogate the function of an organ.

Full-term Pregnancy Induces a Specific Genomic Signature in the Human Breast

“…Cluster C represents differentiation-associated genes whose level of expression continuously and progressively increases with time of pregnancy, reaching their highest levels between 21 and 42 days postpartum, and cluster D comprises genes that are up-regulated around the 15th day of pregnancy and become progressively down-regulated from the end of pregnancy until the 42nd day postpartum (25). These observations confirm at genomic level our previous morphologic and physiologic findings indicating that temporal and sequential changes have to occur in the development of the mammary gland for accomplishing a protective degree of differentiation (11,12,(25)(26)(27)(28). The importance of identifying a specific signature by 42 days postpartum is highlighted by the observations that administration of the polycyclic hydrocarbon 7,12-dimethylbenz(a)anthracene to parous rats results in a markedly reduced tumorigenic response, supporting the concept that the differentiation induced by pregnancy shifts the susceptible ''intermediate cells '' that originate mammary cancer in the terminal end buds of the virginal gland (5, 10) to transformation-resistant cells (11,12).…”

Risk factors according to estrogen receptor status of breast cancer patients in Trivandrum, South India

“…Both pregnancy and breastfeeding have long-term protective effects against breast cancer because of the increased differentiation of breast tissue under the effect of female hormonesmainly progesterone. [48][49][50][51] Increased age of marriage leads to a lack of differentiation in the breast tissue making it more susceptible to harmful effects of nonestrogenic mutagens as well as genotoxic effects of estrogen, which has been known to cause ER2 breast cancers as well. 52,53 Moreover, being married and having children might also reduce the level of circulating hormones or increase the levels of sex hormone-binding globulin.…”

Breast Arterial Calcification Is Associated with Reproductive Factors in Asymptomatic Postmenopausal Women

“…The first full-term birth creates a specific genomic signature in the breast that is protective for breast cancer, especially when the first birth occurs at a young age. 19 This genomic signature is still evident at menopause. 20 Breast tissue also undergoes postlactational involution and an agerelated involution after menopause.…”