Postpartum breast involution reveals regression of secretory lobules mediated by tissue-remodeling

Abstract

IntroductionA postpartum diagnosis of breast cancer is an independent predictor of metastases, however the reason is unknown. In rodents, the window of postpartum mammary gland involution promotes tumor progression, suggesting a role for breast involution in the poor prognosis of human postpartum breast cancers. Rodent mammary gland involution is characterized by the programmed elimination of the secretory lobules laid down in preparation for lactation. This tissue involution process involves massive epithelial cell death, stromal remodeling, and immune cell infiltration with similarities to microenvironments present during wound healing and tumor progression. Here, we characterize breast tissue from premenopausal women with known reproductive histories to determine the extent, duration and cellular mechanisms of postpartum lobular involution in women.MethodsAdjacent normal breast tissues from premenopausal women (n = 183) aged 20 to 45 years, grouped by reproductive categories of nulliparous, pregnant and lactating, and by time since last delivery were evaluated histologically and by special stain for lobular area, lobular type composition, apoptosis and immune cell infiltration using computer assisted quantitative methods.ResultsHuman nulliparous glands were composed dominantly of small (approximately 10 acini per lobule) and medium (approximately 35 acini per lobule) sized lobules. With pregnancy and lactation, a >10 fold increase in breast epithelial area was observed compared to nulliparous cases, and lactating glands were dominated by mature lobules (>100 acini per lobule) with secretory morphology. Significant losses in mammary epithelial area and mature lobule phenotypes were observed within 12 months postpartum. By 18 months postpartum, lobular area content and lobule composition were indistinguishable from nulliparous cases, data consistent with postpartum involution facilitating regression of the secretory lobules developed in preparation for lactation. Analyses of apoptosis and immune cell infiltrate confirmed that human postpartum breast involution is characterized by wound healing-like tissue remodeling programs that occur within a narrowed time frame.ConclusionsHuman postpartum breast involution is a dominant tissue-remodeling process that returns the total lobular area of the gland to a level essentially indistinguishable from the nulliparous gland. Further research is warranted to determine whether the normal physiologic process of postpartum involution contributes to the poor prognosis of postpartum breast cancer.

Physiologically activated mammary fibroblasts promote postpartum mammary cancer

“…These rodent studies are consistent with the concept that breast cancers can misappropriate normal developmentally regulated programs to their advantage, such as physiologic fibroblast activation during mammary gland involution. Young women's breast cancer may be especially responsive to such developmentally regulated programs owing to the remarkable, physiologic breast remodeling that accompanies gland regression in the postpartum setting (12,13).…”

“…Mammary gland involution is well characterized in rodents (8)(9)(10)(11)(12) and recently described in women (12,13). Involution can be separated broadly into an initial phase of secretory epithelial cell death followed by a stromal remodeling phase that reestablishes the adipocytes and connective tissue as dominant constituents of the nonlactating gland (8,14).…”

Cyclooxygenase-2–dependent lymphangiogenesis promotes nodal metastasis of postpartum breast cancer

“…In rodents and women, the process of postpartum involution is characterized by apoptosis of the mammary epithelium as well as attributes of wound healing, including increased macrophage density and fibrillar collagen deposition (1)(2)(3)(4)(5). These same stromal attributes also associate with tumor progression (1,4,6).…”

Form and Function: how Estrogen and Progesterone Regulate the Mammary Epithelial Hierarchy

“…In both mice and humans, full mammary epithelial maturation occurs during pregnancy, in order to generate complex lobules and specialized epithelial cells in alveoli, which have the ability to synthesize and secrete milk for lactation. Finally, after lactation, evidence suggests that the most mature lobules and differentiated mammary epithelial cells collapse, and the mammary network becomes more similar to the resting state prior to pregnancy [5]. This process of expansion and regression can occur across multiple pregnancies during the reproductive phase of a woman’s lifetime, demonstrating that the epithelial cells of the breast have considerable regenerative abilities.…”