STAT signaling in mammary gland differentiation, cell survival and tumorigenesis

Abstract

The mammary gland is a unique organ that undergoes extensive and profound changes during puberty, menstruation, pregnancy, lactation and involution. The changes that take place during puberty involve large-scale proliferation and invasion of the fat-pad. During pregnancy and lactation, the mammary cells are exposed to signaling pathways that inhibit apoptosis, induce proliferation and invoke terminal differentiation. Finally, during involution the mammary gland is exposed to milk stasis, programed cell death and stromal reorganization to clear the differentiated milk-producing cells. Not surprisingly, the signaling pathways responsible for bringing about these changes in breast cells are often subverted during the process of tumorigenesis. The STAT family of proteins is involved in every stage of mammary gland development, and is also frequently implicated in breast tumorigenesis. While the roles of STAT3 and STAT5 during mammary gland development and tumorigenesis are well studied, others members, e.g. STAT1 and STAT6, have only recently been observed to play a role in mammary gland biology. Continued investigation into the STAT protein network in the mammary gland will likely yield new biomarkers and risk factors for breast cancer, and may also lead to novel prophylactic or therapeutic strategies against breast cancer.

p63 is a prosurvival factor in the adult mammary gland during post-lactational involution, affecting PI-MECs and ErbB2 tumorigenesis

“…First, p63 represses the OSM/ pStat3 axis, known to be the major mediator of apoptosis during early involution. 38 Second, similar to that in other epithelial systems DNp63 most likely interferes with the proapoptotic activity of p53 or TAp73 that are also expressed in mammary cells. 11,12,22,60,61 Furthermore, DNp63 has been shown to directly regulate transcription of apoptosis-related genes.…”

“…7,8,36 First, activated Stat3 is a central mediator of apoptosis at this stage. 7,37,38 Second, p53, which induces apoptosis in a transcription-dependent and -independent manner, 39 has also been strongly implicated in the regulation of mammary involution. 37,[40][41][42] Both of these pathways are enhanced in p63 þ / À mammary glands.…”

“…Stat3 phosphorylation during involution is initiated by the interleukin-6 homologs LIF (signaling through the LIF receptor) and oncostatin M (OSM, signaling through its receptor OSM receptor (OSMR)/gp130 and EGFR). 38 Thus, we tested whether p63 -being a transcription factor -regulates mRNA expression of components of these pathways. Indeed, OSM (but not OSMR, EGFR or LIF) mRNA is upregulated in p63 þ / À glands at both day 1 and day 3 of involution ( Figure 3c).…”

“…16 pStat5 is essential in the mammary gland during the prior stages of pregnancy and progressively declines during lactation and early involution. 38,43 pStat5 is activated by upstream Neuregulin/ErbB signaling. 44,45 In agreement, at involution day 1 neuregulin 1 and 2 (NRG1 and NRG2) genes are repressed in p63 þ / À glands, but no longer at day 3 when their expression has declined even in WT glands (Figure 3d).…”

RIG-I–like receptor LGP2 protects tumor cells from ionizing radiation

“…Many of these constitutively expressed ISGs have been characterized as antiviral genes (11). Recently, enhanced levels of constitutively expressed ISGs have been reported in advanced cancers and were often associated with a poor prognosis related to aggressive tumor growth, metastatic spread, resistance to IR/chemotherapy, or combinations of these factors (11)(12)(13)(14)(15)(16)(17)(18). The studies presented in this report are based on the hypothesis that a specific set of constitutively expressed ISGs, whose enhanced expression is by cytotoxic stress, confers a selective advantage to individual tumor clones (5,9,10,13,19).…”