Triple negative, basal-like breast cancer is highly aggressive and has a poor prognosis. The molecular mechanisms that drive its progression are not well understood and no molecular target has been identified for its prevention or treatment. Recent gene profiling studies showed that immortalized human mammary epithelial cells (HMECs) resemble basal-like breast cancer and are appropriate models for the study of basal-like breast cancer. Thus, our goal is to identify molecular mechanisms that cause basal-like breast carcinogenesis using HMECs. We found that abrogation of autocrine TGF? signaling with the expression of a dominant-negative Rll (DNRII) in telomerase-immortalized HMECs suppressed H-ras-V12-induced senescence-like growth arrest (SLGA). Furthermore, co-expression of DNRII and H-ras-V12 rendered HMECs to become highly tumorigenic and metastatic in vivo whereas HMEC clones that spontaneously escaped H-ras-V12-induced SLGA were only weekly tumorigenic and non-metastatic. Thus, we have generated a series of isogenic HMECs representing a full spectrum of basal-like breast carcinogenesis without directly inactivating p53. To identify candidate genes that may mediate the escape of H-ras-V12- induced SLGA and drive malignant progression, we have determined gene expression profiles of five HMEC lines with different senescent and malignant properties. Among the alterations of many interesting genes are down-regulated p21cip1/waf1 and a group of up-regulated genes in DNRII and DNRII+ras HMECs, whose products are involved the regulation of cell cycle checkpoints and transition through mitosis. Thus we hypothesize that autocrine TGF? signaling is an integral part of cellular anti-transformation network by suppressing the expression of a host of genes that mediate oncogene-induced transformation, and abrogation of autocrine TGF? signaling can promote basal-like breast cancer progression. Utilizing the isogenic HMECs we have generated, we will determine the role of autocrine TGF? signaling in promoting oncogene-induced SLGA, chromatin remodeling, and the regulation of p53 activity. We will also determine how the interactions between TGF?, p21, and p53 pathways may confer the role of TGF? in breast carcinogenesis with in vivo approaches. Our long-term goals are to identify biomarkers for basal-like breast cancer prognosis and novel therapeutics to inhibit basal-like breast cancer metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA075253-14
Application #
7903139
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Salnikow, Konstantin
Project Start
1997-07-15
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
14
Fiscal Year
2010
Total Cost
$218,928
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Biology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Liu, Zhao; Wang, Long; Yang, Junhua et al. (2016) Estrogen receptor alpha inhibits senescence-like phenotype and facilitates transformation induced by oncogenic ras in human mammary epithelial cells. Oncotarget 7:39097-39107
Biswas, Tanuka; Gu, Xiang; Yang, Junhua et al. (2014) Attenuation of TGF-? signaling supports tumor progression of a mesenchymal-like mammary tumor cell line in a syngeneic murine model. Cancer Lett 346:129-38
Mishra, S; Deng, J J; Gowda, P S et al. (2014) Androgen receptor and microRNA-21 axis downregulates transforming growth factor beta receptor II (TGFBR2) expression in prostate cancer. Oncogene 33:4097-106
Dong, Qiaoxiang; Wang, Danhan; Bandyopadhyay, Abhik et al. (2013) Mammospheres from murine mammary stem cell-enriched basal cells: clonal characteristics and repopulating potential. Stem Cell Res 10:396-404
Mu, Xiaoxin; Lin, Shu; Yang, Junhua et al. (2013) TGF-? signaling is often attenuated during hepatotumorigenesis, but is retained for the malignancy of hepatocellular carcinoma cells. PLoS One 8:e63436
Roy, Sudipa; Chakravarty, Dimple; Cortez, Valerie et al. (2012) Significance of PELP1 in ER-negative breast cancer metastasis. Mol Cancer Res 10:25-33
Liu, Zhao; Bandyopadhyay, Abhik; Nichols, Robert W et al. (2012) Blockade of Autocrine TGF-? Signaling Inhibits Stem Cell Phenotype, Survival, and Metastasis of Murine Breast Cancer Cells. J Stem Cell Res Ther 2:1-8
Bandyopadhyay, Abhik; Dong, Qiaoxiang; Sun, Lu-Zhe (2012) Stem/progenitor cells in murine mammary gland: isolation and functional characterization. Methods Mol Biol 879:179-93
Mahlawat, Pardeep; Ilangovan, Udayar; Biswas, Tanuka et al. (2012) Structure of the Alk1 extracellular domain and characterization of its bone morphogenetic protein (BMP) binding properties. Biochemistry 51:6328-41
Lin, Shu; Yang, Junhua; Elkahloun, Abdel G et al. (2012) Attenuation of TGF-? signaling suppresses premature senescence in a p21-dependent manner and promotes oncogenic Ras-mediated metastatic transformation in human mammary epithelial cells. Mol Biol Cell 23:1569-81

Showing the most recent 10 out of 37 publications