Pregnancy and Breast Cancer: when They Collide

Women of childbearing age experience an increased breast cancer risk associated with a completed pregnancy. For younger women, this increase in breast cancer risk is transient and within a decade after parturition a cross over effect results in an ultimate protective benefit. The post-partum peak of increased risk is greater in women with advanced maternal age. Further, their lifetime risk for developing breast cancer remains elevated for many years, with the cross over to protection occurring decades later or not at all. Breast cancers diagnosed during pregnancy and within a number of years post-partum are termed pregnancy-associated or PABC. Contrary to popular belief, PABC is not a rare disease and could affect up to 40,000 women in 2009. The collision between pregnancy and breast cancer puts women in a fear-invoking paradox of their own health, their pregnancy, and the outcomes for both. We propose two distinct subtypes of PABC: breast cancer diagnosed during pregnancy and breast cancer diagnosed post-partum. This distinction is important because emerging epidemiologic data highlights worsened outcomes specific to post-partum cases. We reported that post-partum breast involution may be responsible for the increased metastatic potential of post-partum PABC. Increased awareness and detection, rationally aggressive treatment, and enhanced understanding of the mechanisms are imperative steps toward improving the prognosis for PABC. If we determine the mechanisms by which involution promotes metastasis of PABC, the post-partum period can be a window of opportunity for intervention strategies

Studies of postpartum mammary gland involution reveal novel pro-metastatic mechanisms

Postpartum involution is the process by which the lactating mammary gland returns to the pre-pregnant state after weaning. Expression of tumor-promotional collagen, upregulation of matrix metalloproteinases, infiltration of M2 macrophages, and remodeling of blood and lymphatic vasculature are all characteristics shared by the involuting mammary gland and breast tumor microenvironment. The tumor promotional nature of the involuting mammary gland is perhaps best evidenced by cases of postpartum breast cancer (PPBC), or those cases diagnosed within 10 years of most recent childbirth. Women with PPBC experience more aggressive disease and higher risk of metastasis than nulliparous patients and those diagnosed outside the postpartum window. Semaphorin 7a (SEMA7A), cyclooxygenase-2 (COX-2), and collagen are all expressed in the involuting mammary gland and, together, predict for decreased metastasis free survival in breast cancer. Studies investigating the role of these proteins in involution have been important for understanding their contributions to PPBC. Postpartum involution thus represents a valuable model for the identification of novel molecular drivers of PPBC and classical cancer hallmarks. In this review, we will highlight the similarities between involution and cancer in the mammary gland, and further define the contribution of SEMA7A/COX-2/collagen interplay to postpartum involution and breast tumor progression and metastasis

Chitinase 3-like 1 stimulates macrophage-mediated lymphatic remodeling in triple-negative breast cancer

Tumor cells often rely on lymphatic vessels as a transportation route to form distant metastases. Tumor-associated macrophages (TAMs) play an important role in this lymphatic spreading by attaching and integrating into the lymphatic vessel structure, allowing metastatic tumor cells to invade the lymphatics. This process is referred to as macrophage-mediated lymphatic remodeling and can be promoted by specific proteins with macrophage-stimulating and angiogenic properties. The role of chitinase 3-like 1 (CHI3L1), a potent activator of macrophages towards a protumorigenic and angiogenic phenotype, in the macrophage-mediated lymphatic remodeling process has not yet been investigated. Here, we show at first that recombinant (rm)CHI3L1 stimulates macrophages to express podoplanin (PDPN), a characteristic prerequisite marker for lymphatic integration. Additional in vitro analyses showed that rmCHI3L1-treated macrophages adhere more frequently to human-derived lymphatic endothelial cells (HDLECs) in 2D cocultures. Moreover, upon 3D coculturing with HDLEC-derived vessel-like structures on Matrigel® pads, rmCHI3L1-treated macrophages showed increased ability to cluster on and integrate into these in vitro lymphatics. Blocking of the CHI3L1 receptor IL-13Rα2 or PDPN with specific antibodies reduced the rmCHI3L1-stimulated macrophage adhesion to HDLECs and integration into vessel-like structures. Lymphatic TAM integration was further evaluated in primary tumors from a 4T1-based mouse model for triple-negative breast cancer (TNBC) through dual color immunohistochemistry for F4/80+ TAMs and LYVE-1+ lymphatic endothelial cells. The lymphatic integration was affected upon CHI3L1 blockade with chitin or anti-CHI3L1 antibodies. In conclusion, our data identify CHI3L1 as a stimulator of macrophage-mediated lymphatic remodeling and a candidate target to reduce lymphatic (TNBC) metastasis

Cancer Cell CD44 Mediates Macrophage/Monocyte-Driven Regulation of Head and Neck Cancer Stem Cells

Tumor-associated macrophages (TAM) in the tumor microenvironment (TME) cooperate with cancer stem cells (CSC) to maintain stemness. We recently identified cluster of differentiation 44 (CD44) as a surface marker defining head and neck squamous cell carcinoma (HNSCC) CSC. PI3K-4EBP1-SOX2 activation and signaling regulate CSC properties, yet the upstream molecular control of this pathway and the mechanisms underlying cross-talk between TAM and CSC in HNSCC remain largely unknown. Because CD44 is a molecular mediator in the TME, we propose here that TAM-influenced CD44 signaling could mediate stemness via the PI3K-4EBP1-SOX2 pathway, possibly by modulating availability of hyaluronic acid (HA), the main CD44 ligand. HNSCC IHC was used to identify TAM/CSC relationships, and in vitro coculture spheroid models and in vivo mouse models were used to identify the influence of TAMs on CSC function via CD44. Patient HNSCC-derived TAMs were positively and negatively associated with CSC marker expression at noninvasive and invasive edge regions, respectively. TAMs increased availability of HA and increased cancer cell invasion. HA binding to CD44 increased PI3K-4EBP1-SOX2 signaling and the CSC fraction, whereas CD44-VCAM-1 binding promoted invasive signaling by ezrin/PI3K. In vivo, targeting CD44 decreased PI3K-4EBP1-SOX2 signaling, tumor growth, and CSC. TAM depletion in syngeneic and humanized mouse models also diminished growth and CSC numbers. Finally, a CD44 isoform switch regulated epithelial-to-mesenchymal plasticity as standard form of CD44 and CD44v8-10 determined invasive and tumorigenic phenotypes, respectively. We have established a mechanistic link between TAMs and CSCs in HNSCC that is mediated by CD44 intracellular signaling in response to extracellular signals. SIGNIFICANCE: These findings establish a mechanistic link between tumor cell CD44, TAM, and CSC properties at the tumor-stroma interface that can serve as a vital area of focus for target and drug discovery