scholarly journals Insight into mammary gland development and tumor prevention in a newly developed metastatic mouse model of breast cancer

2021 ◽  
Author(s):  
Briana To ◽  
Carson Broeker ◽  
Jing-Ru Jhan ◽  
Rachel Rempel ◽  
Jonathan P Rennhack ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Mouse Model ◽  
Cyclin D1 ◽  
Mammary Gland Development ◽  
Mammary Tumors ◽  
Mammary Development ◽  
Conditional Knockout ◽  
Altered Regulation ◽  
Gland Development

The development of breast cancer has been observed due to altered regulation of mammary gland developmental processes. Thus, a better understand of the normal mammary gland development can reveal possible mechanism in how normal cells are re-programmed to become malignant cells. E2F1-4 are part of the E2F transcription factor family with varied roles in mammary development. However, little is known about the role of E2F5 in mammary gland development. A combination of scRNAseq and predictive signature tools demonstrate the presence of E2F5 in the mammary gland and showed altered activity during the various phases of mammary gland development and function. Testing the hypothesis that E2F5 regulates mammary function, we generated a mammary-specific E2F5 knockout mouse model, resulting in modest mammary gland development changes. However, after a prolonged latency the E2F5 conditional knockout mice developed highly metastatic mammary tumors with metastases in both the lung and liver. Transplantation of the tumors revealed metastases to lymph nodes that was enriched through serial transplantation. Through whole genome sequencing and RNAseq analysis we identified, and then confirmed in vivo, that Cyclin D1 was dysregulated in E2F5 conditional knockout mammary glands and tumors. Based on these findings, we propose that loss of E2F5 leads altered regulation of Cyclin D1, which facilitates the development of mammary tumors.

scholarly journals Progesterone Receptor Isoforms A and B: Temporal and Spatial Differences in Expression during Murine Mammary Gland Development

Endocrinology ◽  
2005 ◽  
Vol 146 (8) ◽  
pp. 3577-3588 ◽  
Author(s):  
Mark D. Aupperlee ◽  
Kyle T. Smith ◽  
Anastasia Kariagina ◽  
Sandra Z. Haslam
Keyword(s):  
Mammary Gland ◽  
Progesterone Receptor ◽  
Cyclin D1 ◽  
Mammary Gland Development ◽  
Minor Role ◽  
Normal Mammary Gland ◽  
Temporal Separation ◽  
Stage Of Development ◽  
Gland Development

Abstract Progesterone is a potent mitogen in the mammary gland. Based on studies using cells and animals engineered to express progesterone receptor (PR) isoforms A or B, PRA and PRB are believed to have different functions. Using an immunohistochemical approach with antibodies specific for PRA only or PRB only, we show that PRA and PRB expression in mammary epithelial cells is temporally and spatially separated during normal mammary gland development in the BALB/c mouse. In the virgin mammary gland when ductal development is active, the only PR protein isoform expressed was PRA. PRA levels were significantly lower during pregnancy, suggesting a minor role at this stage of development. PRB was abundantly expressed only during pregnancy, during alveologenesis. PRA and PRB colocalization occurred in only a small percentage of cells. During pregnancy there was extensive colocalization of PRB with 5-bromo-2′-deoxyuridine (BrdU) and cyclin D1; 95% of BrdU-positive cells and 83% of cyclin D1-positive cells expressed PRB. No colocalization of PRA with either BrdU or cyclin D1 was observed at pregnancy. In the virgin gland, PRA colocalization with BrdU or cyclin D1 was low; only 27% of BrdU-positive cells and 4% of cyclin D1-positive cells expressed PRA. The implication of these findings is that different actions of progesterone are mediated in PRB positive vs. PRA-positive cells in vivo. The spatial and temporal separation of PR isoform expression in mouse mammary gland provides a unique opportunity to determine the specific functions of PRA vs. PRB in vivo.

scholarly journals A Functional Connection between pRB and Transforming Growth Factor β in Growth Inhibition and Mammary Gland Development

2009 ◽  
Vol 29 (16) ◽  
pp. 4455-4466 ◽  
Author(s):  
Sarah M. Francis ◽  
Jacqueline Bergsied ◽  
Christian E. Isaac ◽  
Courtney H. Coschi ◽  
Alison L. Martens ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Growth Factor ◽  
Growth Inhibition ◽  
Mammary Gland Development ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Mammary Development ◽  
Functional Connection ◽  
Gland Development

ABSTRACT Transforming growth factor β (TGF-β) is a crucial mediator of breast development, and loss of TGF-β-induced growth arrest is a hallmark of breast cancer. TGF-β has been shown to inhibit cyclin-dependent kinase (CDK) activity, which leads to the accumulation of hypophosphorylated pRB. However, unlike other components of TGF-β cytostatic signaling, pRB is thought to be dispensable for mammary development. Using gene-targeted mice carrying subtle missense changes in pRB (Rb1 ΔL and Rb1NF ), we have discovered that pRB plays a critical role in mammary gland development. In particular, Rb1 mutant female mice have hyperplastic mammary epithelium and defects in nursing due to insensitivity to TGF-β growth inhibition. In contrast with previous studies that highlighted the inhibition of cyclin/CDK activity by TGF-β signaling, our experiments revealed that active transcriptional repression of E2F target genes by pRB downstream of CDKs is also a key component of TGF-β cytostatic signaling. Taken together, our work demonstrates a unique functional connection between pRB and TGF-β in growth control and mammary gland development.

Apoptosis in mammary gland and cancer.

2000 ◽  
pp. 257-269 ◽  
Author(s):  
R Kumar ◽  
R K Vadlamudi ◽  
L Adam
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Mammary Gland Development ◽  
Expression Profiles ◽  
Critical Role ◽  
Physiological Mechanism ◽  
Cell Loss ◽  
Normal Mammary Gland ◽  
Organ Systems ◽  
Gland Development

Homeostasis in normal tissue is regulated by a balance between proliferative activity and cell loss by apoptosis. Apoptosis is a physiological mechanism of cell loss that depends on both pre-existing proteins and de novo protein synthesis, and the process of apoptosis is integral to normal mammary gland development and in many diseases, including breast cancer. The mammary gland is one of the few organ systems in mammals that completes its morphologic development postnatally during two discrete physiologic states, puberty and pregnancy. The susceptibility of the mammary gland to tumorigenesis is influenced by its normal development, particularly during stages of puberty and pregnancy that are characterized by marked alterations in breast cell proliferation and differentiation. Numerous epidemiologic studies have suggested that specific details in the development of the mammary gland play a critical role in breast cancer risk. Mammary gland development is characterized by dynamic changes in the expression profiles of Bcl-2 family members. The expression of Bcl-2 family proteins in breast cancer is also influenced by estradiol and by progestin. Since the ratio of proapoptotic to antiapoptotic proteins determines apoptosis or cell survival, hormone levels may have important implications in the therapeutic prevention of breast cancer.

scholarly journals Progesterone and Overlooked Endocrine Pathways in Breast Cancer Pathogenesis

Endocrinology ◽  
2015 ◽  
Vol 156 (10) ◽  
pp. 3442-3450 ◽  
Author(s):  
Cathrin Brisken ◽  
Kathryn Hess ◽  
Rachel Jeitziner
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Hormone Receptor ◽  
Cell Activation ◽  
Mammary Gland Development ◽  
Breast Cancer Incidence ◽  
Menstrual Cycles ◽  
Hormone Receptor Positive ◽  
Gland Development

Worldwide, breast cancer incidence has been increasing for decades. Exposure to reproductive hormones, as occurs with recurrent menstrual cycles, affects breast cancer risk, and can promote disease progression. Exogenous hormones and endocrine disruptors have also been implicated in increasing breast cancer incidence. Numerous in vitro studies with hormone-receptor-positive cell lines have provided insights into the complexities of hormone receptor signaling at the molecular level; in vivo additional layers of complexity add on to this. The combined use of mouse genetics and tissue recombination techniques has made it possible to disentangle hormone action in vivo and revealed that estrogens, progesterone, and prolactin orchestrate distinct developmental stages of mammary gland development. The 2 ovarian steroids that fluctuate during menstrual cycles act on a subset of mammary epithelial cells, the hormone-receptor-positive sensor cells, which translate and amplify the incoming systemic signals into local, paracrine stimuli. Progesterone has emerged as a major regulator of cell proliferation and stem cell activation in the adult mammary gland. Two progesterone receptor targets, receptor activator of NfκB ligand and Wnt4, serve as downstream paracrine mediators of progesterone receptor-induced cell proliferation and stem cell activation, respectively. Some of the findings in the mouse have been validated in human ex vivo models and by next-generation whole-transcriptome sequencing on healthy donors staged for their menstrual cycles. The implications of these insights into the basic control mechanisms of mammary gland development for breast carcinogenesis and the possible role of endocrine disruptors, in particular bisphenol A in this context, will be discussed below.

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