Stromal Effects on Mammary Gland Development and Breast Cancer

Wiseman, Bryony; Werb, Zena

doi:10.1126/science.1067431

Cited by 714 publications

(606 citation statements)

References 47 publications

Supporting

Mentioning

571

Contrasting

Unclassified

Order By: Relevance

“…Ablation of SK4, however, had a minor effect on mean survival rates but did not significantly prolong tumour‐free survival nor overall survival in the MMTV‐PyMT tg/+ model (Fig. 4), possibly due to an impaired immune and/or stromal cell response, which results in a tumour progression‐promoting microenvironment (Jinushi et al ., 2011; Loeffler et al ., 2006; Wiseman and Werb, 2002) that counteracts the loss of the oncogenic SK4 functions in the tumour cells. The difference in tumour formation time between SK4‐deficient and SK4‐proficient MMTV‐PyMT tumour cells transplanted orthotopically into WT mice strongly supports this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

et al. 2017

View full text Add to dashboard Cite

Oncogenic signalling via Ca2+‐activated K+ channels of intermediate conductance (SK4, also known as KCa3.1 or IK) has been implicated in different cancer entities including breast cancer. Yet, the role of endogenous SK4 channels for tumorigenesis is unclear. Herein, we generated SK4‐negative tumours by crossing SK4‐deficient (SK4 KO) mice to the polyoma middle T‐antigen (PyMT) and epidermal growth factor receptor 2 (cNeu) breast cancer models in which oncogene expression is driven by the retroviral promoter MMTV. Survival parameters and tumour progression were studied in cancer‐prone SK4 KO in comparison with wild‐type (WT) mice and in a syngeneic orthotopic mouse model following transplantation of SK4‐negative or WT tumour cells. SK4 activity was modulated by genetic or pharmacological means using the SK4 inhibitor TRAM‐34 in order to establish the role of breast tumour SK4 for cell growth, electrophysiological signalling, and [Ca2+]i oscillations. Ablation of SK4 and TRAM‐34 treatment reduced the SK4‐generated current fraction, growth factor‐dependent Ca2+ entry, cell cycle progression and the proliferation rate of MMTV‐PyMT tumour cells. In vivo, PyMT oncogene‐driven tumorigenesis was only marginally affected by the global lack of SK4, whereas tumour progression was significantly delayed after orthotopic implantation of MMTV‐PyMT SK4 KO breast tumour cells. However, overall survival and progression‐free survival time in the MMTV‐cNeu mouse model were significantly extended in the absence of SK4. Collectively, our data from murine breast cancer models indicate that SK4 activity is crucial for cell cycle control. Thus, the modulation of this channel should be further investigated towards a potential improvement of existing antitumour strategies in human breast cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Interestingly, loss of normal epithelial function was followed by remarkable alterations in the stromal compartment including a marked decrease in the number of fat cells and an increase in the number of fibroblasts associated with abnormally high amounts of collagen deposition. Epithelial-stromal crosstalk is crucial for normal mammary gland development (Silberstein, 2001) and altered epithelial-stromal interactions can contribute to cancer progression (Wiseman and Werb, 2002). These experiments represent an example of the fundamental parallels between pubertal mammary gland development and tumor initiation and progression: imbalanced proliferative and apoptotic rates, aberrant cell cycle control, DNA damage checkpoint activation, cellular disorganization and stromal alterations are all characteristics of abnormal development and carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…The developing mammary gland displays many properties related to tumor progression such as invasion of the terminal end bud (TEB) through the fat pad (Wiseman and Werb, 2002). TEBs are highly mitotic and motile structures, which aggressively advance through the stroma and branch by bifurcation until they reach the end of the fat pad when they regress and disappear (Hinck and Silberstein, 2005).…”

Section: Introductionmentioning

confidence: 99%

Loss of cyclin D1 in concert with deregulated estrogen receptor α expression induces DNA damage response activation and interrupts mammary gland morphogenesis

et al. 2007

View full text Add to dashboard Cite

We have previously shown that increased and deregulated estrogen receptor a expression in the mammary gland leads to the development of proliferative disease and cancer. To address the importance of cyclin D1 in ERa-mediated mammary tumorigenesis, we crossed ERa-overexpressing mice with cyclin D1 knockout mice. Mammary gland morphogenesis was completely interrupted in the ERa-overexpressing cyclin D1-deficient triple transgenic mice. In addition to a highly significant reduction in mammary epithelial cell proliferation, cyclin E was upregulated resulting in DNA damage checkpoint activation and apoptosis. This imbalance between proliferative and apoptotic rates in conjunction with remarkable structural defects and cellular disorganization in the terminal end buds interrupted ductal morphogenesis. Interestingly, the structure of the mammary fat pad was fundamentally altered by the consequences of overexpressing ERa in the epithelial cells in the absence of cyclin D1 illustrating how alterations in the epithelial compartment can impact surrounding stromal composition. Transplantation of embryonic ERa-overexpressing and cyclin D1-deficient mammary epithelium into the cleared fat pad of wild-type mice did not rescue the aberrant mammary gland phenotype indicating that it was intrinsic to the mammary epithelial cells. In conclusion, although cyclin D1 is not essential for proliferation of normal mammary epithelial cells, ERa-overexpressing cells are absolutely dependent on cyclin D1 for proliferation. This differential requirement for cyclin D1 in normal vs abnormal mammary epithelial cells supports the application of cyclin D1 inhibitors as therapeutic interventions in ERa-overexpressing breast cancers.

show abstract

“…The mammary gland is unique among ductal epithelial organs in that its development occurs postnatally (Wiseman and Werb, 2002). Before the onset of puberty, the mammary gland is a rudimentary organ consisting of a primitive network of ductal epithelium.…”

Section: Introductionmentioning

confidence: 99%

Candidate regulators of mammary branching morphogenesis identified by genome‐wide transcript analysis

Kouros-Mehr¹,

Werb

2006

Developmental Dynamics

Self Cite

201

177

View full text Add to dashboard Cite

The mammary gland develops in a process known as branching morphogenesis, whereby a distal epithelial bud extends and bifurcates to form an extensive ductal network. Compared with other branched organs, such as the lung and kidney, little is known about the molecular basis of branching in the mammary gland. Here we report a microarray profiling strategy to identify novel genes that may regulate mammary branching. We microdissected terminal end bud (TEB) and mature duct microenvironments from ␤-actin-green fluorescent protein reporter mice and compared their RNA expression profiles with epithelium-free mammary stroma by means of microarray. We identified 1,074 genes enriched in the TEB microenvironment, 222 genes enriched in the mature duct microenvironment, and 385 genes enriched in both TEB and mature duct microenvironments. The microarray correctly predicted the expression of genes known to be enriched in the epithelium (Ets-5) and stroma (MMP-14) of TEBs and in the mature duct microenvironment (MMP-3). The microarray also correctly predicted the localization of previously uncharacterized genes, such as the TEB-enriched SPRR-1a, the duct-enriched casein-␥, and the general epithelial marker pleiotrophin. Analysis of genes enriched in TEBs revealed several genes in the Wnt (Wnt-2, Wnt-5a, Wnt-7b, Dsh-3, Frizzled-1, Frizzled-2), hedgehog (Dhh), ephrin (Ephrin-B1, Eph-A2), and transcription factor (Twist-1, Twist-2, Snail) families. In situ hybridization verified that these genes were enriched in the TEB epithelium (Wnt-5a, Wnt-7b, Dhh, Eph-A2) or TEB stroma (Wnt-2, Frizzled-1, Ephrin-B1). We discuss the potential roles of these genes in mammary branching morphogenesis. Developmental Dynamics 235:3404 -3412, 2006.

show abstract

Stromal Effects on Mammary Gland Development and Breast Cancer

Cited by 714 publications

References 47 publications

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

Loss of cyclin D1 in concert with deregulated estrogen receptor α expression induces DNA damage response activation and interrupts mammary gland morphogenesis

Candidate regulators of mammary branching morphogenesis identified by genome‐wide transcript analysis

Contact Info

Product

Resources

About

Stromal Effects on Mammary Gland Development and Breast Cancer

Cited by 714 publications

References 47 publications

SK4 channels modulate Ca2+ signalling and cell cycle progression in murine breast cancer

SK4 channels modulate Ca2+ signalling and cell cycle progression in murine breast cancer

Loss of cyclin D1 in concert with deregulated estrogen receptor α expression induces DNA damage response activation and interrupts mammary gland morphogenesis

Candidate regulators of mammary branching morphogenesis identified by genome‐wide transcript analysis

Contact Info

Product

Resources

About

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer