Non-steroidal anti-inflammatory drugs target the pro-tumorigenic extracellular matrix of the postpartum mammary gland

Abstract

Breast cancer patients diagnosed postpartum have poor prognosis. The postpartum mammary gland undergoes tissue regression to return to the pre-pregnant state. This involution is characterized by wound healing programs known to be tumor promotional in other contexts. Previous studies have shown that mammary extracellular matrix (ECM) from nulliparous rats has tumor suppressive attributes, while mammary ECM from involuting mammary glands is promotional. In models of pregnancy-associated breast cancer, non-steroidal anti-inflammatory drug (NSAID) treatment targeted to postpartum involution inhibits tumor progression, in part by suppressing COX-2 dependent collagen deposition. Because mammary ECM proteins are coordinately regulated, NSAID treatment is anticipated to result in additional protective changes in the mammary extracellular matrix. Here, systemic NSAID treatment was utilized during postpartum involution to reduce mammary COX-2 activity. ECM was isolated from actively involuting glands of rats treated with NSAIDs and compared to ECM isolated from control-involution and nulliparous rats in 3D cell culture and xenograft assays. Compositional changes in ECM between groups were identified by proteomics. In four distinct 3D culture assays, normal and transformed mammary epithelial cells plated in NSAID-involution ECM, phenocopied cells plated in ECM from nulliparous rats rather than ECM from control-involution rats. Tumor cells mixed with NSAID-involution ECM and injected orthotopically in mice formed smaller tumors than cells mixed with control-involution ECM. Proteomic analyses identified and 3D culture assays implicated the ECM protein tenascin-C as a potential mediator of tumor progression during involution that is decreased by NSAID treatment. In summary, NSAID treatment decreases tumor-promotional attributes of postpartum involution mammary ECM.

Calpains mediate epithelial-cell death during mammary gland involution: mitochondria and lysosomal destabilization

“…Focusing on the changes observed in tissue regression and remodeling, mRNA levels of tenascin-C, a glycoprotein known to be upregulated during involution, 30 were measured. The expression of this extracellular matrix protein was lower in calpeptin samples compared to vehicle controls (Figure 7c).…”

Subcutaneous administration of ketoprofen delays Ehrlich solid tumor growth in mice

“…Thus, the inhibition of these processes has become a potential target in cancer prevention and treatment (O'Brien et al, 2011;Zerbini et al, 2011;Hossain et al, 2011).…”

“…Some studies indicate that the use of COX inhibitors is a major form of therapy in the treatment of human tumors in vitro and in vivo (O'Brien et al, 2011;Zerbini et al, 2011;Hossain et al, 2011). In breast oncology, recent studies demonstrate the therapeutic effects of these compounds as preventive agents and/or for chemotherapy, but data are conflicting (O'Brien et al, 2011;Bosco et al, 2011;Li et al, 2012).…”

“…In breast oncology, recent studies demonstrate the therapeutic effects of these compounds as preventive agents and/or for chemotherapy, but data are conflicting (O'Brien et al, 2011;Bosco et al, 2011;Li et al, 2012).…”

Postlactational Involution: Molecular Mechanisms and Relevance for Breast Cancer Development

“…In addition, these implants showed augmented ibrillar collagen accumulation and high cyclooxygenase-2 (COX-2) expression [52]. Coincidently, in the postlactating mammary gland, inhibition of COX-2 reduced the collagen ibrillogenesis, as well as tumor development and cancer cell invasiveness [53]. Therefore, it has been proposed that women at high risk for postpartum breast cancer might beneit from treatment with nonsteroidal anti-inlammatory drugs (NSAIDs) during postpartum, which would reduce COX-2 expression and its consequences on the behavior of breast initiated cells.…”