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Aberrant activation of NF-κB signaling in mammary epithelium leads to abnormal growth and ductal carcinoma in situ.

Barham W, Chen L, Tikhomirov O, Onishko H, Gleaves L, Stricker TP, Blackwell TS, Yull FE - BMC Cancer (2015)

Bottom Line: We found that even a short pulse of NF-κB activation could induce profound remodeling of mammary ductal structures.These results indicate that aberrant NF-κB activation within mammary epithelium can lead to molecular and morphological changes consistent with the earliest stages of breast cancer.Thus, inhibition of NF-κB signaling following acute inflammation or the initial signs of hyperplastic ductal growth could represent an important opportunity for breast cancer prevention.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, 23rd Ave S and Pierce PRB 325, Nashville, TN, 37232, USA. Whitney.Barham@vanderbilt.edu.

ABSTRACT

Background: Approximately 1 in 5 women diagnosed with breast cancer are considered to have in situ disease, most often termed ductal carcinoma in situ (DCIS). Though recognized as a risk factor for the development of more invasive cancer, it remains unclear what factors contribute to DCIS development. It has been shown that inflammation contributes to the progression of a variety of tumor types, and nuclear factor kappa B (NF-κB) is recognized as a master-regulator of inflammatory signaling. However, the contributions of NF-κB signaling to tumor initiation are less well understood. Aberrant up-regulation of NF-κB activity, either systemically or locally within the breast, could occur due to a variety of commonly experienced stimuli such as acute infection, obesity, or psychological stress. In this study, we seek to determine if activation of NF-κB in mammary epithelium could play a role in the formation of hyperplastic ductal lesions.

Methods: Our studies utilize a doxycycline-inducible transgenic mouse model in which constitutively active IKKβ is expressed specifically in mammary epithelium. All previously published models of NF-κB modulation in the virgin mammary gland have been constitutive models, with transgene or knock-out present throughout the life and development of the animal. For the first time, we will induce activation at later time points after normal ducts have formed, thus being able to determine if NF-κB activation can promote pre-malignant changes in previously normal mammary epithelium.

Results: We found that even a short pulse of NF-κB activation could induce profound remodeling of mammary ductal structures. Short-term activation created hyperproliferative, enlarged ducts with filled lumens. Increased expression of inflammatory markers was concurrent with the down-regulation of hormone receptors and markers of epithelial differentiation. Furthermore, the oncoprotein mucin 1, known to be up-regulated in human and mouse DCIS, was over-expressed and mislocalized in the activated ductal tissue.

Conclusions: These results indicate that aberrant NF-κB activation within mammary epithelium can lead to molecular and morphological changes consistent with the earliest stages of breast cancer. Thus, inhibition of NF-κB signaling following acute inflammation or the initial signs of hyperplastic ductal growth could represent an important opportunity for breast cancer prevention.

No MeSH data available.


Related in: MedlinePlus

Abnormal ducts induced in fully adult, virgin glands through activation of NF-κB in mammary epithelium. 16 week old adult, virgin IKMV and control females, which were previously untreated, were given dox (1 g/L) for 10 days prior to sacrifice. A subtle enlargement of ducts can be seen in haematoxylin stained whole mounts (left panels). The phenotype is more apparent in H&E stained sections (100 μm calibration bar) (right panels). IKMV ducts are filled with cells and significantly larger than the controls. Size of ducts is quantified below images (n = 3 control and n = 3 IKMV glands, total of 64 ducts were measured; ***p = 0.0003)
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Fig5: Abnormal ducts induced in fully adult, virgin glands through activation of NF-κB in mammary epithelium. 16 week old adult, virgin IKMV and control females, which were previously untreated, were given dox (1 g/L) for 10 days prior to sacrifice. A subtle enlargement of ducts can be seen in haematoxylin stained whole mounts (left panels). The phenotype is more apparent in H&E stained sections (100 μm calibration bar) (right panels). IKMV ducts are filled with cells and significantly larger than the controls. Size of ducts is quantified below images (n = 3 control and n = 3 IKMV glands, total of 64 ducts were measured; ***p = 0.0003)

Mentions: As 6 week old virgin mice are still undergoing puberty, the mammary tissue may be responding to a higher level of hormonal stimulation than quiescent, adult glands. To determine if the phenotype would also occur in adult mice, we treated 16 week old virgin IKMV and control females with dox for 10 days. Upon collection, we saw that the IKMV ducts were significantly larger than the control ducts in cross sectional area and had indeed become filled with cells (Fig. 5). This indicated that the notable changes in the IKMV ductal structure after a short-term induction of NF-κB activity were not dependent on puberty-related physiological factors.Fig. 5


Aberrant activation of NF-κB signaling in mammary epithelium leads to abnormal growth and ductal carcinoma in situ.

Barham W, Chen L, Tikhomirov O, Onishko H, Gleaves L, Stricker TP, Blackwell TS, Yull FE - BMC Cancer (2015)

Abnormal ducts induced in fully adult, virgin glands through activation of NF-κB in mammary epithelium. 16 week old adult, virgin IKMV and control females, which were previously untreated, were given dox (1 g/L) for 10 days prior to sacrifice. A subtle enlargement of ducts can be seen in haematoxylin stained whole mounts (left panels). The phenotype is more apparent in H&E stained sections (100 μm calibration bar) (right panels). IKMV ducts are filled with cells and significantly larger than the controls. Size of ducts is quantified below images (n = 3 control and n = 3 IKMV glands, total of 64 ducts were measured; ***p = 0.0003)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4590702&req=5

Fig5: Abnormal ducts induced in fully adult, virgin glands through activation of NF-κB in mammary epithelium. 16 week old adult, virgin IKMV and control females, which were previously untreated, were given dox (1 g/L) for 10 days prior to sacrifice. A subtle enlargement of ducts can be seen in haematoxylin stained whole mounts (left panels). The phenotype is more apparent in H&E stained sections (100 μm calibration bar) (right panels). IKMV ducts are filled with cells and significantly larger than the controls. Size of ducts is quantified below images (n = 3 control and n = 3 IKMV glands, total of 64 ducts were measured; ***p = 0.0003)
Mentions: As 6 week old virgin mice are still undergoing puberty, the mammary tissue may be responding to a higher level of hormonal stimulation than quiescent, adult glands. To determine if the phenotype would also occur in adult mice, we treated 16 week old virgin IKMV and control females with dox for 10 days. Upon collection, we saw that the IKMV ducts were significantly larger than the control ducts in cross sectional area and had indeed become filled with cells (Fig. 5). This indicated that the notable changes in the IKMV ductal structure after a short-term induction of NF-κB activity were not dependent on puberty-related physiological factors.Fig. 5

Bottom Line: We found that even a short pulse of NF-κB activation could induce profound remodeling of mammary ductal structures.These results indicate that aberrant NF-κB activation within mammary epithelium can lead to molecular and morphological changes consistent with the earliest stages of breast cancer.Thus, inhibition of NF-κB signaling following acute inflammation or the initial signs of hyperplastic ductal growth could represent an important opportunity for breast cancer prevention.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, 23rd Ave S and Pierce PRB 325, Nashville, TN, 37232, USA. Whitney.Barham@vanderbilt.edu.

ABSTRACT

Background: Approximately 1 in 5 women diagnosed with breast cancer are considered to have in situ disease, most often termed ductal carcinoma in situ (DCIS). Though recognized as a risk factor for the development of more invasive cancer, it remains unclear what factors contribute to DCIS development. It has been shown that inflammation contributes to the progression of a variety of tumor types, and nuclear factor kappa B (NF-κB) is recognized as a master-regulator of inflammatory signaling. However, the contributions of NF-κB signaling to tumor initiation are less well understood. Aberrant up-regulation of NF-κB activity, either systemically or locally within the breast, could occur due to a variety of commonly experienced stimuli such as acute infection, obesity, or psychological stress. In this study, we seek to determine if activation of NF-κB in mammary epithelium could play a role in the formation of hyperplastic ductal lesions.

Methods: Our studies utilize a doxycycline-inducible transgenic mouse model in which constitutively active IKKβ is expressed specifically in mammary epithelium. All previously published models of NF-κB modulation in the virgin mammary gland have been constitutive models, with transgene or knock-out present throughout the life and development of the animal. For the first time, we will induce activation at later time points after normal ducts have formed, thus being able to determine if NF-κB activation can promote pre-malignant changes in previously normal mammary epithelium.

Results: We found that even a short pulse of NF-κB activation could induce profound remodeling of mammary ductal structures. Short-term activation created hyperproliferative, enlarged ducts with filled lumens. Increased expression of inflammatory markers was concurrent with the down-regulation of hormone receptors and markers of epithelial differentiation. Furthermore, the oncoprotein mucin 1, known to be up-regulated in human and mouse DCIS, was over-expressed and mislocalized in the activated ductal tissue.

Conclusions: These results indicate that aberrant NF-κB activation within mammary epithelium can lead to molecular and morphological changes consistent with the earliest stages of breast cancer. Thus, inhibition of NF-κB signaling following acute inflammation or the initial signs of hyperplastic ductal growth could represent an important opportunity for breast cancer prevention.

No MeSH data available.


Related in: MedlinePlus