Role of Chromatin Regulator in Breast Cell Growth

Institution: University of California, Davis
Investigator(s): Hongwu Chen, Ph.D. -
Award Cycle: 2001 (Cycle VII) Grant #: 7KB-0140 Award: $286,151
Award Type: New Investigator Awards
Research Priorities
Biology of the Breast Cell>Biology of the Normal Breast: the starting point

Initial Award Abstract (2001)
Breast cancer poses an enormous threat to womenís health yet, its cause and the means for a cure have remained undiscovered. It is therefore extremely important to identify new factors that control the growth of both normal and cancer breast cells, in order to find the cure.

Growth of both normal and cancer cells requires the synthesis of large number of different proteins using the genetic information carried on DNA. DNA in human cells is organized into a structure called chromatin. Recent study indicates that the flow of genetic information from DNA to make cellular proteins is highly controlled at the chromatin structure level by a group of proteins. In addition, normal breast cells, like other normal human cells, have a limited life span.

We have recently found that one of the chromatin regulator proteins can increase the growth rate of breast cancer cells. We have also observed that altered function of this regulator protein can prolong the life span of normal breast cells when cultured in the laboratory settings. More importantly, the level of this protein has been found highly elevated in clinical breast tumors. Taken together, these evidences appear to suggest that this chromatin regulator protein plays important roles in both the control of normal breast cell growth and initiation and/or progression of breast cancer.

The key question we are asking is how the chromatin regulator protein controls normal cell life span and enhances breast tumor cell growth. We will examine what are the cell life-span control mechanisms affected by the chromatin regulator protein in normal breast cells, and analyze what are the effects on gene activities, breast cancer cell growth and response to therapeutic hormones such as tamoxifen if the function of this regulator protein is altered. Finally, we will dissect the key elements in this regulator protein to provide valuable information for future drug design.

Our observations that this regulator protein can prolong the life span of normal breast cells and enhance breast cancer cell proliferation are very recent ones. These results represent new findings for identification of factors involved in control of breast cell growth. Our concept that alteration of the chromatin structure that controls the flow of genetic information could be key factors causing cancer is a novel idea and needs to be fully investigated.

Final Report (2006)
Aberration of gene expression is a frequent event detected in malignant cells. However, the consequences are often not well understood. ACTR/AIB1, a member of the p160/SRC transcriptional coactivator gene family, was found overexpressed and/or amplified in over 30% of primary breast tumor samples. ACTR interacts directly with the nuclear hormone receptors including estrogen receptors (ERs). Thus, it was conceivable that ACTR/AIB1 might play an important role in control of hormone-stimulated human mammary epithelial cell proliferation. However, whether ACTR/AIB1 overexpreession plays a causal role in promoting breast cancer development and progression has not been determined. Our initial results indicated that ectopic expression of ACTR in non-malignant human mammary epithelial cells (HMECs) transiently extends their lifespan and that ACTR overexpression in ER-positive breast cancer cells markedly enhances estrogen-stimulated cell proliferation. Therefore, we hypothesize that ACTR/AIB1 could play important roles both in normal human breast cell growth and in breast cancer development and progression.

We obtained several results that support the conclusion that elevated level/function of ACTR can prolong the lifespan of HMEC. First, with the stable HMEC sub-lines that express elevated levels of ACTR, we confirmed our initial observation that elevated ACTR could transiently extend the lifespan of HMECs in cell culture. However, due to the transient nature of the effect, we were unable to further dissect the molecular mechanism of ACTR action in prolonging HMEC lifespan, despite repeated attempts. Secondly, through depletion of ACTR by RNAi, we found that ACTR is required for normal human breast epithelial cell growth. With regard to Aim 2, we made the following findings that directly address the role of ACTR in breast cancer cell proliferation and its oncogenicity:

(1) We found that elevated level of ACTR can stimulate the proliferation of breast cancer cells both in presence and in the absence of estrogen and ER.
(2) More strikingly, we found that high levels of ACTR can overcome the growth inhibitory effect of anti-estrogens in ER positive cells.
(3) We also found that ACTR interacts with the key cell cycle regulatory protein E2F and plays an important role in control of cell cycle progression in cancer cells.
(4) Our genome-wide search for ACTR target genes identified novel genes involved in promoting breast cancer cell proliferation.

Our finding that overexpressed ACTR may interact directly with key cell cycle regulators, independent of ER, to promote breast cancer cell proliferation suggests that disrupting the interaction between ACTR and the cell cycle regulator such as E2F represents a new therapeutic strategy for breast cancer with aberrant ACTR function. We also hope that the identification of novel ACTR target genes can provide unexpected targets for therapeutic interventions of breast cancers.

Symposium Abstract (2003)
The development of breast cancer involves multiple genetic alterations including the inactivation of tumor suppressor function and the aberrant activation of genes associated with promoting cell proliferation and survival. ACTR/AIB1, a member of the SRC-1/p160 nuclear receptor coactivators, was recently found to be up-regulated through gene amplification and/or over-production in over 30% of breast cancers. However, the mechanism through which elevated levels of ACTR/AIB1 play a role in the initiation and/or progression of breast and cancer is unclear. Since the p160 coactivators physically interact with members of the nuclear receptor family including estrogen receptors, it has been postulated that the overexpression of the coactivator may promote hormone-dependent cancer cell proliferation.

We report here that elevation of ACTR level in hormone-responsive breast cancer cells not only enhances their estrogen-stimulated proliferation, but, more significantly, promotes their growth in the absence of hormone. Surprisingly, we found that elevated levels of ACTR render the cells resistant to anti-estrogens-induced growth suppression. Results of our further study show that ACTR physically associates with the cell cycle regulatory proteins such as transcription factor E2F1 and may function as an E2F1 coactivator to stimulate some of the key E2F1target gene expression. Our findings suggest that amplification/overexpression of ACTR/AIB1 may play an important role in the progression of breast cancer to anti-estrogen resistance.

ACTR/AIB1 fuctions as an E2F1 coactivator to promote breast cancer cell proliferation and anti-estrogen resistance
Periodical:Molecular and Cellular Biology
Index Medicus: Mol Cell Biol
Authors: Louie MC, Zou JX, Rabinovich A, Chen HW
Yr: 2004 Vol: 24 Nbr: 12 Abs: Pg:5157-5171

Direct control of cell cycle gene expression by proto-oncogene ACTR adn its auto-regulation underlying its transforming activity
Periodical:Molecular and Cellular Biology
Index Medicus: Mol Cell Biol
Authors: Louie MC, Revenko A, Yao J, Zou JX, Chen HW
Yr: 2006 Vol: 26 Nbr: 10 Abs: Pg:3810-23