Pamela Cowin, PhD
Professor of Cell Biology and Dermatology
PhD, 1984 Southampton University, U.K.
Cancer Stem Cells, Signal Transduction, Stem Cell Biology, Segmentation and Pattern Formation, Mammary Development
Mammary Stem Cells; Cancer Stem Cells; Wnt; Hedgehog; Ltbp; GPCR
Mammary glands form in the embryo but also undergo extensive postnatal ductal development during puberty. Each pregnancy induces proliferation and differentiation to generates temporary ductal branches and milk producing alveoli. At the end of lactation a process of involution removes these temporary structures by programed cell death and extensive extracellular matrix remodeling. This cycle of mammary development is regulated temporally by hormones but spatially by the secretion of hormonally-induced local paracrine factors. We study the roles of Wnt/β-catenin Hedgehog/Gli and Ltbp/TGFβ pathways in this process.
β-catenin promotes cadherin cell adhesion at the plasma membrane but acts as a transcription factor in the nucleus. Cadherin-catenin complexes maintain epithelial integrity in the developing mammary gland and their loss or transient downregulation occurs frequently in human breast cancer invasion and metastasis. Numerous signaling pathways regulate the stability of cytosolic β-catenin, the best understood being the canonical Wnt pathway. Wnts stabilize cytosolic β-catenin and promote its nuclear entry and transcriptional function. Wnt/β-catenin signaling regulates normal mammary stem cell dynamics and is essential for embryonic and postnatal mammary development. Our work has shown that deregulated β-catenin signaling leads to mammary stem and progenitor cell accumulation, precocious development and breast cancer in mice. Recent studies suggest that a similar link exists between reactivation of developmental pathways and human metaplastic and basal subtypes of breast cancer, which have the worst prognosis and patient outcome. Deregulated β-catenin signaling can occur by other signaling routes, and importantly many of these pathways are aberrant in breast cancer and when disturbed also cause mammary developmental abnormalities.
In addition we study links between Wnt and Hedgehog signaling in the mammary gland and our work has shown that repression of Hedgehog signaling is critical for normal embryonic mammary development. Misactivation of this pathway in the embryo leads to loss and malformation of mammary buds. Currently we are studying the effects of derepressing this pathway during adult mammary development and our studies have shown that gain of Hedgehog signaling creates a cancer stem cell niche that supports Wnt tumor induction.
TGFβ inhibits mammary stem cell proliferation but promotes breast cancer metastasis. We are studying how its master regulator Ltbp1 may generate a prometastatic environment during particular windows of breast developmental known to be linked to elevated breast cancer risk.
Chandramouli A, Simundza J, Pinderhughes A, Hiremath M, Droguett G, Frendewey D, Cowin P. 2013. Ltbp1L is focally induced in embryonic mammary mesenchyme, demarcates the ductal luminal lineage and is upregulated during involution. Breast Cancer Res. 2013 Nov 21;15(6):R111. [Epub ahead of print] PMID: 24262428
Chandramouli A, Hatsell SJ, Pinderhughes A, Koetz L, Cowin P. 2013 Gli activity is critical at multiple stages of embryonic mammary and nipple development. PLoS One. 2013 Nov 18;8(11):e79845. PMID: 24260306 PMCID: PMC3832531
Anton, Roman; Chatterjee, Sujash S; Simundza, Julia; Cowin, Pamela; Dasgupta, Ramanuj. (2011) A Systematic Screen for Micro-RNAs Regulating the Canonical Wnt Pathway. PLoS ONE 2011 ;6(10):e26257. PMID: 22043311
Chandramouli, Anupama; Simundza, Julia; Pinderhughes, Alicia; Cowin, Pamela. (2011) Choreographing Metastasis to the Tune of LTBP. Journal of mammary gland biology & neoplasia 2011 Jun;16(2):67-80. PMID: 21494784
Mukherjee, Atish; Soyal, Selma M; Li, Jie; Ying, Yan; Szwarc, Maria M; He, Bin; Kommagani, Ramakrishna; Hodgson, Myles C; Hiremath, Minoti; Cowin, Pamela; Lydon, John P. (2011) A mouse transgenic approach to induce beta-catenin signaling in a temporally controlled manner. Transgenic research 2011 Aug;20(4):827-840. PMID: 21120693
Wu, Xinyu; Chen, Fei; Sahin, Aysegul; Albarracin, Constance; Pei, Zhiheng; Zou, Xuanyi; Singh, Baljit; Xu, Ruliang; Daniels, Garrett; Li, Yirong; Wei, Jianjun; Blake, Marvin; Schneider, Robert J; Cowin, Pamela; Lee, Peng. (2011) Distinct function of androgen receptor coactivator ARA70alpha and ARA70beta in mammary gland development, and in breast cancer. Breast cancer research & treatment 2011 Jul;128(2):391-400. PMID: 20814820
Cowin, Pamela;Wysolmerski, John. (2010) "Molecular mechanisms guiding embryonic mammary gland development". Cold Spring Harbor perspectives in biology. 2: a003251. PMID: 20484386
Teissedre, Brigitte; Pinderhughes, Alicia; Incassati, Angela; Hatsell, Sarah J; Hiremath, Minoti; Cowin, Pamela. (2009) "MMTV-Wnt1 and -DeltaN89beta-catenin induce canonical signaling in distinct progenitors and differentially activate Hedgehog signaling within mammary tumors". PLoS ONE. 4: e4537. PMID: 19225568
Hiremath, Minoti; Lydon, John P; Cowin, Pamela. (2007) "The pattern of beta-catenin responsiveness within the mammary gland is regulated by progesterone receptor". Development. 134: 3703. PMID: 17881490