Involvement of Different networks in mammary gland involution after the pregnancy/lactation cycle: Implications in breast cancer

Abstract

Early pregnancy is associated with a reduction in a woman's lifetime risk for breast cancer. However, different studies have demonstrated an increase in breast cancer risk in the years immediately following pregnancy. Early and long-term risk is even higher if the mother age is above 35 years at the time of first parity. The proinflammatory microenvironment within the mammary gland after pregnancy renders an "ideal niche" for oncogenic events. Signaling pathways involved in programmed cell death and tissue remodeling during involution are also activated in breast cancer. Herein, the major signaling pathways involved in mammary gland involution, signal transducer and activator of transcription (STAT3), nuclear factorkappa B (NF-jB), transforming growth factor beta (TGFb), and retinoid acid receptors (RARs)/retinoid X receptors (RXRs), are reviewed as part of the complex network of signaling pathways that crosstalk in a contextual-dependent manner. These factors, also involved in breast cancer development, are important regulatory nodes for signaling amplification after weaning. Indeed, during involution, p65/p300 target genes such as MMP9, Capn1, and Capn2 are upregulated. Elevated expression and activities of these proteases in breast cancer have been extensively documented. The role of these proteases during mammary gland involution is further discussed. MMPs, calpains, and cathepsins exert their effect by modification of the extracellular matrix and intracellular proteins. Calpains, activated in the mammary gland during involution, cleave several proteins located in cell membrane, lysosomes, mitochondria, and nuclei favoring cell death. Besides, during this period, Capn1 is most probably involved in the modulation of preadipocyte differentiation through chromatin remodeling. Calpains can be implicated in cell anchoring loss, providing a proper microenvironment for tumor growth. A better understanding of the role of any of these proteases in tumorigenesis may yield novel therapeutic targets or prognostic markers for breast cancer. V C 2015 IUBMB Life, 67(4): [227][228][229][230][231][232][233][234][235][236][237][238] 2015 Keywords: Apoptosis; Calpains; NF-jB; STATs; programmed cell death; Tissue remodeling Mammary Gland in the Pregnancy/ Lactation Cycle: A General OverviewThe mammary gland is composed of epithelial cells: luminal, alveolar, and myoepithelial; together with mesenchymal cells which include adipocytes, fibroblasts, endothelial cells from blood vessels, and macrophages. At puberty, the gland expands to form a highly branched tubular structure that is subtended by fat. During the pregnancy/lactation cycle, the mammary gland expands further, and the branched tubular

Reproductive Risk Factors of Inflammatory Breast Cancer according to Luminal, HER2-Overexpressing, and Triple-Negative Subtypes: A Case Comparison Study

“…Mammary gland involution after the pregnancy-lactation cycle increases the duration of the breast remodeling period, with an increase in mammary progenitor cells and anti-inflammatory mediators [26]. High blood flow to the mammary gland for a long period of time between pregnancy and weaning may be favorable for a vascular tropism of cell proliferation and clonal expansion and after years may lead to breast cancer with vascular emboli and inflammatory aspect [27].…”

Tetramethylpyrazine regulates breast cancer cell viability, migration, invasion and apoptosis by affecting the activity of Akt and caspase-3

“…The major signaling pathways involved in mammary gland involution, signal transducer and activator of transcription (STAT3), nuclear factor-kappa B (NF-κB), transforming growth factor beta (TGF-β), and retinoid acid receptors (RARs)/retinoid X receptors (RXRs), are reviewed as part of the complex network of signaling pathways that crosstalk in a contextual-dependent manner. These factors, also involved in breast cancer development, and are important regulatory nodes for signaling amplification following weaning (8). A previous study demonstrated that the application of a single molecule is unlikely to suppress the cross-talk between cancerous cells (9).…”

Postlactational Involution: Molecular Mechanisms and Relevance for Breast Cancer Development

“…During mammary gland involution and cancer progression, these proteins are relevant for modifying the extracellular matrix, allowing tissue remodeling and/or cell invasion. In addition, calpains also cleave intracellular proteins located in the cell membrane, lysosomes, mitochondria, and nuclei, favoring cell death during involution and cell anchoring loss during tumor progression [62].…”