Investigating the role of STAT3 in promoting precancerous changes in abruptly involuted mouse mammary glands
Loading...
Date
2019-05
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
The Ohio State University
Abstract
Breast cancer is the most common cancer in women and is the second most common cancer overall. Currently, there is a cancer disparity between Caucasian women (CW) and African American Women (AAW). AAW have a higher incidence of triple negative breast cancer (TNBC), an aggressive breast cancer subtype associated with high mortality and characterized by lack of estrogen receptor (ER-), progesterone receptor (PR-), and human epidermal growth factor receptor 2 (HER2-).
Epidemiological studies have shown that lack, or short duration, of breast-feeding, a more common practice among AAW than CW, may be one of the many factors that increases the risk of TNBC in women. The human pregnancy-lactation-involution cycle is a dynamic process where breast undergoes extensive alveologenesis, milk production and programmed cell death. Upon cessation of breastfeeding, the mammary gland undergoes involution as it remodels to near pre-pregnant state. Prolonged breastfeeding results in gradual remodeling (Gradual Involution, GI) whereas no or short duration of breastfeeding leads to forced and abrupt remodeling (Abrupt involution, AI) of the mammary gland. The mechanistic difference between GI and AI and the link between AI and breast cancer remains unclear.
We modeled GI and AI of mammary gland in wild-type FVB/N mice. GI and AI females were allowed to nurse the pups for 28 days or 7 days respectively. AI but not GI led to the development of precancerous changes in the mammary glands within 4 months postpartum, without additional oncogenic events. Notably, AI glands demonstrated persistent expansion of mammary luminal progenitor (LP) epithelial cells, putative cells of origin of TNBC/ basal-like tumors. On day28 and day56 postpartum, there was persistent increase in Stat3 (Signal Transducer and Activator of Transcription 3) activation (pStat3Y705) in the AI glands.
Persistent activation of STAT3 has been linked to an increase in tumor cell proliferation, survival, invasion, and tumor-promoting inflammation. In mice, Stat3 is required for the initiation and acute phase response of involution and is crucial for the proliferation of LP population
We hypothesized that Stat3 activation plays a key role in the development of precancerous changes observed in AI. We bred Stat3Fl/Fl mice with MMTV-Cre mice to induce epithelial deletion of Stat3. Experimental (MMTV-Cre+;Stat3Fl/Fl) and control females (Stat3Fl/Fl) were then subjected to AI. Mammary glands were harvested on postpartum day28, day56, and day120.
Evaluation of haematoxylin and eosin stained sections and collagen deposition, using Masson’s Trichrome protocol, revealed that Stat3 deletion did not abrogate the increased hyperplasia and collagen deposition we initially observed in our AI model with intact Stat3. Fluorescence activated cell sorting of mammary epithelial cells demonstrated that Stat3 deletion resulted in reduction of LP cell population at early time point (day28), while these cells were replenished in glands harvested on day56 and120. Immunohistochemistry analysis of cell proliferation, using anti-Ki67, found no significant changes in cell proliferation at all timepoints.
While further studies are underway, our data suggests that Stat3 may diminish the effects of AI on mouse mammary gland.
Description
Keywords
Stat3, Breast Cancer, Breastfeeding, Awareness, Mechanism