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Review
. 2014 Jan 25;382(1):560-569.
doi: 10.1016/j.mce.2013.03.014. Epub 2013 Mar 28.

STAT signaling in mammary gland differentiation, cell survival and tumorigenesis

S Haricharan  1 , Y Li  2
Affiliations
Review

STAT signaling in mammary gland differentiation, cell survival and tumorigenesis

S Haricharan et al. Mol Cell Endocrinol. .

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, programmed 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.

Keywords: Breast cancer; Involution; Lactation; Mammary gland development; Pregnancy; STATs.

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Figures

Figure 1
Figure 1. The STAT family of proteins regulates every stage of mammary gland development during a reproductive cycle
During early pregnancy, STAT6, activated by cytokines IL-4 and IL-13, initiates alveolar lineage commitment. These alveolar cells activate STAT5 primarily via PRL-PRLR. pSTAT5 institutes a transcriptional program that results in lactation. At the end of lactation, the loss of the suckling triggers a STAT3-dependent apoptotic program to remove the differentiated alveolar cells. STAT3 is activated by LIF during the initial stages of involution, and by OncostatinM in the later stages. While the expression patterns of the various STATs often overlaps, in this diagram each STAT has been placed in the reproductive cycle according to its maximal impact on mammary gland development. Key activating and downstream proteins are included.
Figure 2
Figure 2. STAT1 and STAT6 may be important regulators of breast tumorigenesis
The various stages during breast tumor development and progression are depicted along a single duct, going from normal epithelium, through hyperplasia, DCIS, tumor and finally tumor growth and metastasis. STAT1, which is probably activated by interferons, is a tumor suppressor. However, STAT1 also promotes tumor resistance to therapy by suppressing the DNA damage response (DDR) pathway. STAT6, which is activated by IL-4, induces the differentiation of T-helper type 2 cells, which promotes tumor establishment and metastasis.
Figure 3
Figure 3. STAT3 stimulates breast cancer cell survival, proliferation, invasiveness and metastasis
STAT3 is a known oncogene with several diverse tumorigenic functions. The downstream effectors of STAT3 in promoting tumor growth, stemness, metastasis and angiogenesis are depicted. Grey cells represent stem cell-like cells in the tumor. The blood vessel is drawn in red.
Figure 4
Figure 4. STAT5 plays distinct roles during tumor initiation and tumor progression
STAT5 promotes tumor initiation, while it also promotes differentiation of established cancer cells. Cells that have sustained an oncogenic insult are depicted pink. On sustaining an oncogenic insult, pSTAT5− cells (white) may undergo cell death (pink with jagged edge), but pSTAT5+ cells (grey) are able to overcome oncogene-induced apoptosis, thereby evolving into a differentiated tumor (pink) with good prognosis. Known downstream mediators are depicted in the accompanying pathways, while potential effectors are noted with a question mark.
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