The Rodent Liver Undergoes Weaning-Induced Involution and Supports Breast Cancer Metastasis

Goddard, Erica T.; Hill, Ryan C.; Nemkov, Travis; D’Alessandro, Angelo; Hansen, Kirk C.; Maller, Ori; Mongoue-Tchokote, Solange; Mori, Motomi; Partridge, Ann H.; Borges, Virginia F.; Schedin, Pepper

doi:10.1158/2159-8290.cd-16-0822

Cited by 47 publications

(94 citation statements)

References 35 publications

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“…There is also a distinct visceral pattern of metastasis in PPBC that suggests circulating tumor cells released from the involuting mammary gland have additional metastatic advantages. In postpartum patients, a ~3-fold increase in liver metastasis but not lung, brain or bone is reported (52). This metastatic pattern is consistent with a uniquely hospitable "soil" in the liver of postpartum women.…”

Section: Tumor Promotion During Postpartum Breast Involutionsupporting

confidence: 55%

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

et al. 2020

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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 yoa). Crossover to the protective effect of pregnancy is dependent on age at first pregnancy, with young mothers receiving the most benefit. Further, breast cancer diagnosis during the five-ten-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. Post-partum 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 also 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. Breast Cancer and Pregnancy Cancer is an increasing complication of pregnancy worldwide, in part due to the advancing age of child-bearing women (1-3). Cancer diagnosis during pregnancy is overall a relatively rare event, affecting about 1 in 1000 pregnancies and representing 0.1% or less of all cancers (4). Globally, the most common cancers diagnosed during pregnancy follow the patterns of prevalent cancers in the underlying population. In Western countries, breast, thyroid, and gynecologic cancers, as well as melanoma and lymphomas are the most common (3,5,6). In Asia, the rate of gastric cancer is much higher, and melanoma not reported (7,8). Great progress has been made in advancing the ability to safely treat pregnant women with excellent guidelines and reviews available across many cancers (1,6-10). Of the cancers that affect woman during the childbearing life-window, only breast cancer and melanoma have been implicated as being increased in frequency, specifically among postpartum women, in comparison to age-matched peers (11). Breast cancer is globally the most frequent cancer diagnosed during pregnancy and in the postpartum years, and therefore the most studied. However, the impact of pregnancy on breast cancer is substantially more than the complexity of managing those diagnosed during pregnancy and, to date, it is only breast cancer where parity status has been shown to influence prognosis. This review will focus on the complex and varied interactions between pregnancy and breast cancer with emphasis on breast cancer ...

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Section: Tumor Promotion During Postpartum Breast Involutionsupporting

confidence: 55%

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

et al. 2020

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“…Of potential relevance, the risk of developing breast cancer is increased in the postpartum window, and cancers that develop postpartum have poorer prognoses than breast cancers in age-matched nulliparous women, even after matching for tumor stage and biologic subtype (9). Further, in rodent models, the immune milieu of the involuting gland has been implicated in progression of postpartum tumors (24,54,67). Our study finds that immune tolerance, which may be executed by tolerogenic dendritic cells, is enhanced during weaning-induced involution, implicating immune tolerance as one potential mechanism of mammary tumor promotion.…”

Section: Discussionmentioning

confidence: 99%

Mucosal Immunity in the Female Murine Mammary Gland

Betts

Pennock

Caruso

et al. 2018

The Journal of Immunology

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The mammary gland is not classically considered a mucosal organ, although it exhibits some features common to mucosal tissues. Notably, the mammary epithelium is contiguous with the external environment, is exposed to bacteria during lactation, and displays antimicrobial features. Nonetheless, immunological hallmarks predictive of mucosal function have not been demonstrated in the mammary gland, including immune tolerance to foreign Ags under homeostasis. This inquiry is important, as mucosal immunity in the mammary gland may assure infant and women's health during lactation. Further, such mucosal immune programs may protect mammary function at the expense of breast cancer promotion via decreased immune surveillance. In this study, using murine models, we evaluated mammary specific mucosal attributes focusing on two reproductive states at increased risk for foreign and self-antigen exposure: lactation and weaning-induced involution. We find a baseline mucosal program of RORγT CD4 T cells that is elevated within lactating and involuting mammary glands and is extended during involution to include tolerogenic dendritic cell phenotypes, barrier-supportive antimicrobials, and immunosuppressive Foxp3 CD4 T cells. Further, we demonstrate suppression of Ag-dependent CD4 T cell activation, data consistent with immune tolerance. We also find Ag-independent accumulation of memory RORγT Foxp3 CD4 T cells specifically within the involution mammary gland consistent with an active immune process. Overall, these data elucidate strong mucosal immune programs within lactating and involuting mammary glands. Our findings support the classification of the mammary gland as a temporal mucosal organ and open new avenues for exploration into breast pathologic conditions, including compromised lactation and breast cancer.

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“…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.…”

Section: Young Patientsmentioning

confidence: 99%

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

Freedman

Partridge

2017

Clinical Cancer Research

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There are distinct subgroups of patients who have historically been underrepresented in most prospective clinical trials in breast cancer, including the youngest and oldest patients, male patients, and those struggling with obesity. Herein, we review current and future directions in research for each of these special populations with breast cancer, highlighting significant knowledge gaps and priorities in tumor biology and heterogeneity, therapeutic decision making promotion of adherence, supportive care, and psychosocial and functional well-being. In younger women, future study should focus on the biological underpinnings of aggressive disease and optimizing adherence and treatment decision making while addressing their unique survivorship needs. The latter includes generating a scientific basis for interruption of therapy for pregnancy. Among older patients, interventions should focus on increasing clinical trial accrual, predicting and mitigating toxicity so that functional status can be optimized, tailoring needs for dose modification, and anticipating life expectancy in the context of competing causes of death. For men with breast cancer, we need worldwide collaboration to answer even basic questions on optimal treatment, supportive care, and survivorship strategies. Finally, for those struggling with obesity, we need to better understand the biological associations with cancer incidence, prognosis and outcome, and how we can best intervene to assure weight loss at the "right time." It is only through highly collaborative, far-reaching, prospective, multidisciplinary, patient-centered, and patient-engaged efforts that we can optimize the physical and psychologic outcomes for all patients with breast cancer.

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The Rodent Liver Undergoes Weaning-Induced Involution and Supports Breast Cancer Metastasis

Cited by 47 publications

References 35 publications

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

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

Mucosal Immunity in the Female Murine Mammary Gland

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

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