Breast cancer is recognized as the most prevalent malignancy among women in North America with a life time risk currently estimated to be one in eight. Most importantly, reproductive history or more specifically steroid hormonal status has been shown to be an important risk factor. Recently, I generated a progesterone receptor (PR) knockout (PRKO) mouse that has demonstrated that progesterone (P), and its receptor, the PR, are absolutely required for normal mammary gland proliferation and differentiation. The involvement of P in mammary tumorigenesis has been a matter of controversy for several years mainly because P can protentiate or inhibit mammary tumorigenesis. To clarify the complex temporal relationship between P and mammary tumorigenesis, the PRKO mouse will be utilized to determine whether the P indued-proliferative signal has a role to play in breast cancer by investigating the effects of removing PR function on mammary tumor progression.
The specific aims of this proposal are to: 1) evaluate whether removal of PR function alters murine susceptibility to carcinogen-induced mammary tumorigenesis at the morphological, histological, and molecular level; 2) determine whether PR function has a role in the development of hormone dependent mammary tumors exhibited by the Grunder mouse and define whether the PR has an involvement in the progression of these tumors to a hormone independent phenotype; and 3) to define the distinct effects of mammary epithelial and stromal derived PR populations on mammary development and tumorigenesis by using reciprocal mammary gland transplantation technology. Apart from advancing our current understanding of P's contribution to mammary tumorigenesis, information from these studies will aid in the design of effective strategies for breast cancer prevention and treatment as well as prompting a reevaluation of the current use of progestins in contraception and postmenopausal hormonal replacement therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA077530-05
Application #
6513371
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Sathyamoorthy, Neeraja
Project Start
1998-04-01
Project End
2005-03-31
Budget Start
2002-04-01
Budget End
2005-03-31
Support Year
5
Fiscal Year
2002
Total Cost
$109,718
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Szwarc, Maria M; Kommagani, Ramakrishna; Jacob, Allison P et al. (2015) Aberrant Activation of the RANK Signaling Receptor Induces Murine Salivary Gland Tumors. PLoS One 10:e0128467
Szwarc, Maria M; Lydon, John P; O'Malley, Bert W (2015) Steroid receptor coactivators as therapeutic targets in the female reproductive system. J Steroid Biochem Mol Biol 154:32-8
Szwarc, Maria M; Kommagani, Ramakrishna; Lessey, Bruce A et al. (2014) The p160/steroid receptor coactivator family: potent arbiters of uterine physiology and dysfunction. Biol Reprod 91:122
Kommagani, Ramakrishna; Szwarc, Maria M; Kovanci, Ertug et al. (2014) A murine uterine transcriptome, responsive to steroid receptor coactivator-2, reveals transcription factor 23 as essential for decidualization of human endometrial stromal cells. Biol Reprod 90:75
Szwarc, Maria M; Kommagani, Ramakrishna; Jeong, Jae-Wook et al. (2014) Perturbing the cellular levels of steroid receptor coactivator-2 impairs murine endometrial function. PLoS One 9:e98664
Bruno, Robert D; Boulanger, Corinne A; Rosenfield, Sonia M et al. (2014) Paracrine-rescued lobulogenesis in chimeric outgrowths comprising progesterone-receptor-null mammary epithelium and redirected wild-type testicular cells. J Cell Sci 127:27-32
Clementi, Caterina; Tripurani, Swamy K; Large, Michael J et al. (2013) Activin-like kinase 2 functions in peri-implantation uterine signaling in mice and humans. PLoS Genet 9:e1003863
Obr, Alison E; Grimm, Sandra L; Bishop, Kathleen A et al. (2013) Progesterone receptor and Stat5 signaling cross talk through RANKL in mammary epithelial cells. Mol Endocrinol 27:1808-24
Nagashima, Takashi; Li, Qinglei; Clementi, Caterina et al. (2013) BMPR2 is required for postimplantation uterine function and pregnancy maintenance. J Clin Invest 123:2539-50
Nagashima, Takashi; Kim, Jaeyeon; Li, Qinglei et al. (2011) Connective tissue growth factor is required for normal follicle development and ovulation. Mol Endocrinol 25:1740-59

Showing the most recent 10 out of 16 publications