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

Abstract

Childbirth at any age confers a transient increased risk for breast cancer in the first decade postpartum and this window of adverse effect extends over two decades in women with late-age first childbirth (>35 years of age). Crossover to the protective effect of pregnancy is dependent on age at first pregnancy, with young mothers receiving the most benefit. Furthermore, breast cancer diagnosis during the 5- to 10-year postpartum window associates with high risk for subsequent metastatic disease. Notably, lactation has been shown to be protective against breast cancer incidence overall, with varying degrees of protection by race, multiparity, and lifetime duration of lactation. An effect for lactation on breast cancer outcome after diagnosis has not been described. We discuss the most recent data and mechanistic insights underlying these epidemiologic findings. Postpartum involution of the breast has been identified as a key mediator of the increased risk for metastasis in women diagnosed within 5-10 years of a completed pregnancy. During breast involution, immune avoidance, increased lymphatic network, extracellular matrix remodeling, and increased seeding to the liver and lymph node work as interconnected pathways, leading to the adverse effect of a postpartum diagnosis. We al discuss a novel mechanism underlying the protective effect of breastfeeding. Collectively, these mechanistic insights offer potential therapeutic avenues for the prevention and/or improved treatment of postpartum breast cancer.

Figure 1.

Graphical presentation of the associations between pregnancy and lactation with breast cancer risk and outcome. While pregnancy confers long term protection in young first mothers, all mothers experience a transient early risk for breast cancer which extends long term in older mothers. Additionally, in those who do not lactate this risk is also increased and there is evidence that prolonged lactation can also decrease long term risk for breast cancer. Finally, if breast cancer is diagnosed in the postpartum decade there is an increased risk for metastasis and death from breast cancer compared with nulliparous or older women, which is not seen among cases diagnosed during pregnancy.

Figure 2.

Model of how lactation, postpartum involution and epithelial cell imprinting of parity intersect to impact incidence and outcomes in postpartum breast cancer (PPBC). Physiologic involution (middle panel), which is mediated in part by pro-tumorigenic TGFbeta, COX-2, SEMA7A and collagen dependent signaling, shares numerous attributes with pro-tumor wound healing, including immune cell infiltrate, immune tolerance, and lymphangiogenesis, resulting in involution being a risk window for poor prognostic breast cancer. Upregulation of molecules with known tumor suppressive functions are present during lactation (left panel) and abrupt cessation of lactation exasperates involution associated programs of inflammation, which contributes to abnormal expression of PAPP-A during involution. The increased deposition of collagen during involution acts to enhance the proteolytic activity of PAPP-A against IGFBP-5 leading to increased IGF and collagen receptor DDR2 signaling and tumor promotion. In contrast, prolonged or gradual cessation of lactation promotes the accumulation of stanniocalin 1 and 2 (STC1, 2), which act as inhibitors of PAPP-A, reducing tumor progression. Mammary epithelial cells are also imprinted by undergoing a reproductive cycle (right panel), which possibly accounts for the increased tumor risk and progression that are elevated for at least 10 years post childbirth. Image courtesy of Sarah E Tarullo, PhD (University of Colorado).