Deciphering Pro-Lymphangiogenic Programs during Mammary Involution and Postpartum Breast Cancer

Abstract

Postpartum breast cancers are a highly metastatic subset of young women’s breast cancers defined as breast cancers diagnosed in the postpartum period or within 5 years of last child birth. Women diagnosed with postpartum breast cancer are nearly twice as likely to develop metastasis and to die from breast cancer when compared with nulliparous women. Additionally, epidemiological studies utilizing multiple cohorts also suggest that nearly half of all breast cancers in women aged <45 qualify as postpartum cases. Understanding the biology that underlies this increased risk for metastasis and death may lead to identification of targeted interventions that will benefit the large number of young women with breast cancer who fall into this subset. Preclinical mouse models of postpartum breast cancer have revealed that breast tumor cells become more aggressive if they are present during the normal physiologic process of postpartum mammary gland involution in mice. As involution appears to be a period of lymphatic growth and remodeling, and human postpartum breast cancers have high peritumor lymphatic vessel density (LVD) and increased incidence of lymph node metastasis (1, 2), we propose that novel insight into is to be gained through the study of the biological mechanisms driving normal postpartum mammary lymphangiogenesis as well as in the microenvironment of postpartum tumors.

Emerging Data and Current Challenges for Young, Old, Obese, or Male Patients with Breast Cancer

“…The particularly higher mortality of these women has been hypothesized to be due to a tumor-promoting microenvironment in the postpartum/lactational, involuting breast. Evolving animal and human data support that mammary involution entails a proin-flammatory process including an active period of lymphatic growth and remodeling, with tumors demonstrating high peritumoral lymphatic vessel density, increased incidence of lymph node metastasis (12)(13)(14)(15), and possible enrichment of liver and brain metastasis in the postpartum period (16). In addition, epidemiologic data reveal that the molecular phenotype of PABC tends to be more aggressive.…”

Dynamic architectural interplay between leucocytes and mammary epithelial cells

“…The few studies that have been carried out on mammary gland blood and lymphatic vasculature have shown that both vessel types are closely apposed to the mammary ducts with the former also penetrating the alveolar buds while the lymphatic network does not . Neolymphangiogenesis has been shown to occur during involution of the mammary gland in concert with upregulation of VEGF‐C, VEGF‐D and their receptors . A recent study showed that the GPI‐anchored membrane glycoprotein semaphorin 7A (SEMA7A) is expressed in the mammary epithelium during involution and suggested that SEMA7A may play a role in macrophage‐mediated lymphangiogenesis .…”

Postpartum breast cancer: mechanisms underlying its worse prognosis, treatment implications, and fertility preservation

“…17 The reason for this inconsistency can be contributed to the definition of the control group as all young women with breast cancer that are diagnosed after 1 year of childbirth, while it has been shown that the poor prognosis associated with a postpartum diagnosis can last up to 10 years. [4][5][6] In this review we will explore whether postpartum breast cancer, defined as breast cancer diagnosed up to 5 to 10 years in women<45 years of age, can be seen as a distinct entity with a unique biology. We will focus on the mechanisms that underly the poor prognosis of postpartum breast cancer, especially those related to mammary gland involution (regression of the mammary gland to its pre-pregnant state).…”

“…3 By this definition, postpartum breast cancer is estimated to represent 50% of breast cancers arising in young mothers within 10 years of their last childbirth. [4][5][6] Age at diagnosis, parity status, and breastfeeding history are among the most important risk factors for postpartum breast cancer. Older age at first birth correlates with an increased risk for postpartum breast cancer.…”