Pregnancy and Breast Cancer: Pathways to Understand Risk and Prevention

Abstract

Several studies have made strong efforts to understand how age and parity modulate the risk of breast cancer. A holistic understanding of the dynamic regulation of the morphological, cellular, and molecular milieu of the mammary gland offers insights into the drivers of breast cancer development as well as into potential prophylactic interventions, the latter being a longstanding ambition of the research and clinical community aspiring to eradicate the disease. In this review we discuss mechanisms that react to pregnancy signals, and we delineate the nuances of pregnancyassociated dynamism that contribute towards either breast cancer development or prevention. Further definition of the molecular basis of parity and breast cancer risk may allow the elaboration of tools to predict and survey those who are at risk of breast cancer development. Parity: A Perspective for Therapeutic and Prophylactic InterventionBreast cancer is the most frequently diagnosed malignance in women. It strikes >1.6 million women worldwide, and about one in eight 8 women in the USA will develop breast cancer in their lifetime (Box 1 and Table 1). Most breast cancers arise because of dysfunction of cells in mammary ducts (50-70% of tumors) or lobules (10-15% of breast cancers), which categorizes these tumors as carcinomas, specifically adenocarcinomas. Some breast tumors are sarcomas, originating in the stroma or muscle. Other types and subtypes of breast cancer are less frequent, and a single diagnosis of breast cancer may refer to a combination of different tumors (www.breastcancer.org) (Box 1).Parity is known to have a dual effect on breast cancer risk. In many ways, breast tumorigenesis mimics several mechanisms that are commonly activated during pregnancy, including augmented cell proliferation, alterations in cell shedding, reduced cell apoptosis, altered gene expression, and extracellular matrix (ECM) modifications. On the other hand, epidemiological studies have provided evidence of the cancer-preventive benefits of pregnancy wherein an early age of pregnancy decreases the risk of breast cancer development. Although understanding the molecular mechanisms underlying these phenomena is still in its infancy, their elucidation will open new avenues to target breast cancer. Mammary Gland Composition and DevelopmentThe mammary gland is a complex and highly adaptive organ whose main function, in female mammals, is to produce milk during lactation for the sustenance of young offspring. The gland is composed of a variety of cell types, including fibroblasts, adipocytes, epithelial, endothelial, and immune cells. The epithelial cells can be further subdivided into multiple cell types that, together, form the branching structure of the gland and constitute the secretory alveoli during lactation. Two main epithelial cell compartments can be distinguished in the mammary gland: the luminal compartment [the inner cell layer, localized between the lumen (see Glossary),and the basal compartment] and the basal compartment (the outer layer surrounding ...

Postpartum Involution and Cancer: An Opportunity for Targeted Breast Cancer Prevention and Treatments?

“…Metrics related to reproductive history are not commonly included in breast cancer clinical data sets, such that the number of breast cancers that meet the definition of PPBC is currently derived from best estimates. One approach to estimate global burden of PPBC is to utilize data obtained from developed countries, which show that ~13% of all breast cancers are YWBC (27,28) and that ~50% of these cases have likely completed a pregnancy within 10 years of their diagnosis (29). This approach results in a global estimation of ~130,000 PPBC cases per year.…”

“…Pregnancy both promotes and protects against breast cancer (29)(30)(31). All parous women are under a 10-30% increased risk of developing breast cancer for at least a decade after childbirth in comparison to nulliparous young women, with older age at first birth increasing the magnitude of risk (31).…”

Emerging roles of N6-methyladenosine (m6A) modification in breast cancer

“…In addition, epidemiological studies have found that reproductive history is linked to the development of breast cancer. The risk of breast cancer is significantly less in early pregnancy (before age 20), while the risk transiently increases after parturition [91,93]. Peri et al [94] have demonstrated that hnRPA2B1 is overexpressed in the mammary tissues of post-menopausal parous women, suggesting that m 6 A modification may contribute to the correlation between pregnancy and breast cancer.…”

Desensitization of human breast progenitors by a transient exposure to pregnancy levels of estrogen

“…In humans an apparent lifelong natural protection is obtained by full term pregnancy somewhat depending on the age at which pregnancy begins 1 . The greatest protection is obtained when the first full term birth occurs before the age of twenty, and parity continues to impact positively until the early thirties (reviewed in 2 , 3 ). The protective effect only pertains to estrogen receptor-positive (ER pos ) breast cancer, which is particularly interesting because of its relatively late onset in postmenopausal women 2 .…”

“…That estrogens play a role in breast cancer prevention is suggested from studies in rodents where artificial imitation of the hormonal milieu of pregnancy confers the same protection as does pregnancy 4 . While the exact molecular mechanisms affording such protection are still far from understood (reviewed in 3 ), it has been speculated that protection relates to either long-lasting cell autonomous alterations in the breast stem cell hierarchy or persistent changes in the systemic or microenvironmental hormonal milieu—or both 2 . Nevertheless, whether ER pos cells participate in conveying this protection has remained an enigmatic question for decades.…”